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Classifications

Harrison's Chapter

ICD-O Morphology

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Mappings

MONDO

MONDO:0020322 acute biphenotypic leukemia Not Yet Curated

MONDO:0020322 (acute biphenotypic leukemia) is the narrower WHO-2001-era term for the single-blast-population co-expression pattern and is a subclass of MONDO:0020743. Issue #7468 cited MONDO:0020322, but this entry is scoped to the full WHO/ICC mixed phenotype acute leukemia family, which also includes the bilineal (two separate blast populations) pattern, so MONDO:0020743 is used as the primary term.

MONDO:0019460 acute leukemia of ambiguous lineage Not Yet Curated

The parent category that additionally contains acute undifferentiated leukemia, which is curated here as a related ambiguous-lineage subtype.

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Subtypes

6

genetically defined

Mixed phenotype acute leukemia with BCR::ABL1 fusion MONDO:0850449

MPAL carrying t(9;22)(q34.1;q11.2) / BCR::ABL1. Recognized as a distinct WHO/ICC entity because the fusion kinase supplies a targetable signaling dependency, and tyrosine kinase inhibitors are added to the treatment backbone.

Show evidence (2 references)

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia with BCR::ABL1 fusion Mixed-phenotype acute leukaemia with KMT2A rearrangement"

WHO-HAEM5 lists MPAL with BCR::ABL1 fusion as one of the two genetically defined ambiguous-lineage entities.

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

In a 100-patient WHO-defined MPAL series t(9;22) was the single most common recurrent lesion, supporting it as a defined subtype.

Mixed phenotype acute leukemia with KMT2A rearrangement MONDO:0850450

MPAL carrying a rearrangement of KMT2A (MLL) at 11q23.3, most often with a B/myeloid immunophenotype. KMT2A fusions enforce an aberrant HOXA/MEIS1 transcriptional program in an immature progenitor, and this subtype is over-represented in infants.

Show evidence (2 references)

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia with BCR::ABL1 fusion Mixed-phenotype acute leukaemia with KMT2A rearrangement"

WHO-HAEM5 lists MPAL with KMT2A rearrangement as the second genetically defined ambiguous-lineage entity.

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

11q23/KMT2A rearrangements were the second most common recurrent cytogenetic lesion in this WHO-defined MPAL series.

Acute leukemia of ambiguous lineage with BCL11B rearrangement

Ambiguous-lineage acute leukemia carrying a structural rearrangement that hijacks an enhancer to BCL11B at 14q32.2. WHO-HAEM5 and the ICC name it as a defined ambiguous-lineage genetic group alongside ZNF384-rearranged disease. It is curated at subtype level rather than folded into the T/myeloid NOS group because the entity spans acute undifferentiated leukemia and T/myeloid MPAL, and reaches into ETP-ALL and AML with minimal differentiation, so it cuts across the immunophenotypically defined subtypes rather than sitting inside one. No MONDO term exists for this entity yet, so no subtype_term is bound.

Show evidence (2 references)

PMID:35732831 SUPPORT Other

"The other subtype is ALAL with BCL11B rearrangement, which has a more heterogenous immunophenotype ... in acute undifferentiated leukaemia (AUL) and ~20-30% of T/myeloid MPAL."

WHO-HAEM5 names ALAL with BCL11B rearrangement as a defined ambiguous-lineage subtype and gives its 20-30% share of T/myeloid MPAL and its overlap with acute undifferentiated leukemia.

PMID:41477275 SUPPORT Other

"with specific subcategories characterized by BCR::ABL1, KMT2A, ZNF384, or BCL11B rearrangements."

A 2025 review lists BCL11B rearrangement among the four genetic subcategories of MPAL, alongside BCR::ABL1, KMT2A and ZNF384.

immunophenotypically defined

Mixed phenotype acute leukemia, B/myeloid, not otherwise specified MONDO:0850451

MPAL meeting WHO/ICC criteria for both B and myeloid lineage assignment without a defining BCR::ABL1 or KMT2A lesion. ZNF384 rearrangements are the most characteristic recurrent alteration in this group.

Show evidence (2 references)

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia, B/myeloid Mixed-phenotype acute leukaemia, T/myeloid Mixed-phenotype acute leukaemia, rare types"

WHO-HAEM5 defines B/myeloid MPAL as one of the immunophenotypically defined ambiguous-lineage entities.

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Genomic profiling establishes ZNF384 rearrangement as the recurrent lesion characteristic of B/myeloid MPAL.

Mixed phenotype acute leukemia, T/myeloid, not otherwise specified MONDO:0850452

MPAL meeting WHO/ICC criteria for both T and myeloid lineage assignment without a defining genetic lesion. Genomically it overlaps substantially with early T-cell precursor ALL, with recurrent WT1, PHF6, RUNX1, ETV6 and NOTCH1 alterations and frequent BCL11B enhancer hijacking.

Show evidence (2 references)

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia, B/myeloid Mixed-phenotype acute leukaemia, T/myeloid Mixed-phenotype acute leukaemia, rare types"

WHO-HAEM5 defines T/myeloid MPAL as an immunophenotypically defined ambiguous-lineage entity.

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Genomic profiling shows T/myeloid MPAL is defined by biallelic WT1 alterations and overlaps early T-cell precursor ALL.

related ambiguous-lineage entity

Acute undifferentiated leukemia (AUL) MONDO:0020321

An acute leukemia of ambiguous lineage in which blasts express no lineage-defining marker at all (no myeloperoxidase, no cytoplasmic CD3, no B-lineage marker combination) and typically carry only immaturity markers such as CD34, HLA-DR and TdT. AUL is not strictly MPAL, since no lineage is assigned rather than more than one, but it sits in the same ambiguous-lineage category and shares the immature-progenitor cell of origin, so it is curated here as a related subtype.

Show evidence (1 reference)

PMID:31982153 SUPPORT Human Clinical

"Acute undifferentiated leukemia (AUL) is rare and defined by the absence of bona fide myeloid and lymphoid markers."

Defines AUL by absence of lineage-defining markers, contrasting with MPAL where more than one lineage is assigned.

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Discussions and Knowledge Gaps

3

Does ALL-directed induction actually outperform AML-directed or hybrid induction in mixed phenotype acute leukemia when tested prospectively, and for which genetic subgroups?

KNOWLEDGE GAP OPEN mpal_no_prospective_randomized_therapy_data

Attached to

treatments#ALL-Type Induction Chemotherapy

Every current recommendation to prefer ALL-type induction derives from retrospective series, registry data and meta-analysis of those series. No prospective controlled trial has compared induction strategies in MPAL, so confounding by indication, era and center cannot be excluded, and the optimal approach for genetically defined subgroups is unknown.

Proposed experiments

Prospective cooperative-group induction-backbone study in centrally reviewed MPAL

exp_mpal_prospective_induction_backbone

Enrol centrally reviewed WHO/ICC MPAL into a cooperative-group protocol that randomizes or risk-stratifies the induction backbone (ALL-type versus AML-type versus hybrid), using end-of-induction measurable residual disease as the primary early endpoint and event-free survival as the confirmatory endpoint.

Decision criterion

A prespecified difference in end-of-induction MRD negativity between induction backbones, confirmed by event-free survival.

Would support

Prospective confirmation that ALL-directed induction is superior would convert the current retrospective recommendation into controlled evidence.

Would refute

Equivalent MRD and survival across backbones would show the retrospective signal reflects confounding by indication, era and center.

Prespecified genetic-subgroup analysis of induction response

exp_mpal_genetic_subgroup_induction_analysis

Within the same prospective cohort, analyse induction response separately by BCR::ABL1, KMT2A, ZNF384 and BCL11B status and by AML-like versus ALL-like methylation class.

Decision criterion

A subgroup-by-backbone interaction that survives prespecified multiplicity control.

Would support

Evidence that induction choice should be genetically rather than immunophenotypically guided.

Would refute

Absence of interaction would support a single uniform backbone for all MPAL.

Show evidence (2 references)

PMID:25605373 SUPPORT Other

"No prospective, controlled trials exist to guide therapy."

States the absence of prospective controlled evidence directly.

PMID:28099272 SUPPORT Other

"Most data that inform therapy are based on retrospective, uncontrolled studies; prospective trials that incorporate targeted approaches based on genetics and immunophenotype are needed."

Confirms the evidence base is retrospective and identifies the trial design needed to close the gap.

What is the optimal induction strategy for acute undifferentiated leukemia, where no lineage is assigned and therefore no lineage-directed regimen is indicated by phenotype?

KNOWLEDGE GAP OPEN mpal_aul_optimal_therapy_unknown

Attached to

has_subtypes#Acute undifferentiated leukemia

The therapeutic logic used in MPAL is to pick the regimen matching an assignable lineage. In AUL no lineage is assignable, so that logic gives no guidance, and population-based data show most AUL patients receive no chemotherapy at all and have the worst adult survival of any acute leukemia.

Proposed experiments

Molecular-class-stratified registry study of acute undifferentiated leukemia

exp_aul_molecular_class_registry

Assemble a prospective registry of centrally reviewed AUL and stratify by DNA methylation and transcriptomic class rather than by immunophenotype, which by definition provides no lineage information in this entity.

Decision criterion

Identification of molecular classes with reproducibly different treatment response or survival.

Would support

A molecular basis for assigning induction therapy in a phenotypically uninformative leukemia.

Would refute

Absence of class-associated outcome differences would argue AUL should be treated as a single high-risk group.

Trial of lineage-agnostic regimens in prospectively identified AUL

exp_aul_lineage_agnostic_regimen_trial

Evaluate BCL2-directed and other lineage-agnostic regimens in prospectively identified AUL, given that most AUL patients currently receive no chemotherapy at all.

Decision criterion

Response rate and overall survival compared with the population-based untreated and chemotherapy-treated AUL benchmarks.

Would support

A deliverable standard of care for a group with the worst adult acute leukemia survival.

Would refute

Lack of activity would redirect effort toward transplant-directed or supportive strategies.

Show evidence (2 references)

PMID:41063702 SUPPORT Other

"For AUL the optimal therapeutic approach is uncertain."

A 2025 review states directly that optimal AUL therapy is undetermined.

PMID:31982153 SUPPORT Human Clinical

"Only 35% of AUL patients had received chemotherapy. Comparatively, 94% of ALL and 71% of AML cases received chemotherapy."

Shows the practical consequence of the gap: most AUL patients are not treated with chemotherapy at all.

If neither genotype nor transcriptome reliably predicts MPAL immunophenotype, should MPAL be classified and treated by immunophenotype at all, or by epigenetic/transcriptional lineage class?

OPEN QUESTION OPEN mpal_immunophenotype_does_not_track_genotype

Attached to

pathophysiology#Stem-like Transcriptional State and Epigenetic Lineage Programming

Multiomic single-cell data show immunophenotype is decoupled from genetic and transcriptional profile, while methylation-defined AML-like versus ALL-like classes predict response to lineage-matched therapy. This challenges the immunophenotypic basis of the current WHO/ICC definition and of therapy selection.

Proposed experiments

Methylation-class-guided versus immunophenotype-guided therapy assignment

exp_mpal_methylation_vs_immunophenotype_assignment

Prospectively assign induction therapy either by the current immunophenotypic lineage call or by AML-like versus ALL-like methylation class, and compare remission and survival.

Decision criterion

Superior complete response or survival in the methylation-guided arm.

Would support

Replacing or supplementing the immunophenotypic definition of MPAL with an epigenetic one for therapeutic purposes.

Would refute

Equivalence would justify retaining immunophenotype as the operational basis of classification and therapy.

Independent validation of the MPAL95 stemness score

exp_mpal95_independent_validation

Validate the 95-gene MPAL95 stemness score as a risk stratifier in an independent prospective MPAL cohort, modelled jointly with end-of-induction measurable residual disease.

Decision criterion

MPAL95 retains independent prognostic value after adjustment for MRD and established clinical covariates.

Would support

Adding a transcriptional stemness axis to MPAL risk stratification.

Would refute

Loss of significance after MRD adjustment would show the score is captured by existing response-based measures.

Show evidence (2 references)

PMID:39294124 SUPPORT Human Clinical

"We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes."

Establishes the decoupling of immunophenotype from underlying molecular state that motivates the question.

PMID:29991687 SUPPORT Human Clinical

"Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given."

Provides the alternative epigenetic classification whose clinical value the question asks to test prospectively.

⚙

Pathophysiology

12

Transformation of an Immature Multipotent Hematopoietic Progenitor

MPAL originates in a hematopoietic stem or multipotent progenitor cell that has not yet committed to a single lineage. Because the cell of origin sits upstream of the myeloid/lymphoid branch point, the founding clone retains access to more than one differentiation program, which is the structural precondition for the ambiguous phenotype that defines the disease.

hematopoietic stem cell CL:0000037 hematopoietic multipotent progenitor cell CL:0000837

hematopoietic progenitor cell differentiation GO:0002244 ⚠ ABNORMAL

Downstream

Failure of Lineage Commitment Transformation of a cell upstream of lineage commitment leaves the normal lineage-specification machinery operating in an uncommitted state.

BCR-ABL1 Kinase-Driven Proliferative Signaling When BCR::ABL1 is acquired in a multipotent rather than a lineage-committed progenitor, the resulting leukemia is ambiguous rather than purely lymphoid or myeloid.

KMT2A Rearrangement and Aberrant HOXA Transcriptional Program KMT2A fusions arising in an immature progenitor produce leukemias with stem-like and mixed-lineage programs.

Show evidence (2 references)

PMID:30209392 SUPPORT Human Clinical

"We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo."

Localizes the founding lesions of MPAL to primitive hematopoietic progenitors rather than to lineage-committed cells.

PMID:35247902 SUPPORT Model Organism

"Expression of ZNF384 FO early in hematopoiesis results in binding and deregulation of key hematopoietic regulators, skewing of hematopoiesis, and priming for leukemic transformation. These results reveal the interplay between cell of origin and expression of ZNF384 FO to mediate lineage..."

Functional mouse and human HSPC modelling shows the cell of origin is a required co-determinant of lineage ambiguity, supporting the causal role this node assigns to the progenitor compartment.

Failure of Lineage Commitment

Normal hematopoietic lineage choice is enforced by mutually antagonistic transcription factor networks (PU.1/SPI1 and CEBPA for myeloid, EBF1 and PAX5 for B, NOTCH1 and BCL11B for T). In MPAL these networks are disrupted or incompletely resolved, so no single program is consolidated and lineage-restricting feedback loops fail to close. The blast is left in a promiscuous, multi-lineage-primed transcriptional state.

hematopoietic multipotent progenitor cell CL:0000837

SPI1 hgnc:11241 PAX5 hgnc:8619 EBF1 hgnc:3126 BCL11B hgnc:13222 NOTCH1 hgnc:7881 RUNX1 hgnc:10471

regulation of myeloid cell differentiation GO:0045637 ⚠ ABNORMAL B cell differentiation GO:0030183 ⚠ ABNORMAL T cell differentiation GO:0030217 ⚠ ABNORMAL

Downstream

Cross-Lineage Antigen Co-expression An unresolved multi-lineage transcriptional program is transcribed and translated into simultaneous expression of myeloid and lymphoid lineage-defining proteins.

Lineage Plasticity and Therapy Escape Because alternative lineage programs remain accessible rather than silenced, the clone can shift lineage under selective pressure.

Stem-like Transcriptional State and Epigenetic Lineage Programming Failure to consolidate a lineage program leaves the blast in the stem-like, high-differentiation-potential transcriptional state that single-cell profiling identifies as the shared feature of MPAL.

Show evidence (3 references)

PMID:30209392 SUPPORT Human Clinical

"These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity."

States explicitly that lineage promiscuity in MPAL is a property of the cell of origin and founding lesion rather than of accumulated mutations, which is the failure-of-commitment model captured by this node.

PMID:31792411 SUPPORT Human Clinical

"Despite widespread epigenetic heterogeneity within the patient cohort, we observe common malignant signatures across patients as well as patient-specific regulatory features that are shared across phenotypic compartments of individual patients."

Single-cell chromatin and transcriptome profiling of MPAL patients shows regulatory features shared across the different phenotypic (lineage) compartments of the same leukemia, consistent with one unresolved multi-lineage program rather than two independent lineage programs.

PMID:39813682 PARTIAL Human Clinical

"Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation."

Supports a transcription-factor-deficit model of failed lineage resolution in mixed-phenotype acute leukemia; marked PARTIAL because the quoted finding is reported for the AML-with-mixed-phenotype group rather than for MPAL proper.

Stem-like Transcriptional State and Epigenetic Lineage Programming

Multiomic single-cell profiling shows that MPAL blasts, irrespective of their surface immunophenotype or driver genotype, converge on a shared stem-cell-like transcriptional program indicating high differentiation potential; the degree of that stemness tracks with survival. Genome-wide methylation separates MPAL into AML-like and ALL-like epigenetic classes whose lineage-commitment gene expression differs, so the epigenetic state, not only the mutation set, determines which lineage programs the blast can access. This node is the mechanistic bridge between a failed commitment decision and both the observed cross-lineage phenotype and the capacity for lineage switch.

hematopoietic multipotent progenitor cell CL:0000837

stem cell differentiation GO:0048863 ⚠ ABNORMAL hemopoiesis GO:0030097 ⚠ ABNORMAL

Downstream

Cross-Lineage Antigen Co-expression An epigenetic state that keeps both myeloid and lymphoid programs accessible is transcribed into simultaneous cross-lineage antigen expression.

Lineage Plasticity and Therapy Escape High differentiation potential is precisely the property that permits a clone to relocate to another lineage under therapeutic pressure.

Clonal Blast Expansion and Bone Marrow Replacement Stem-like self-renewal sustains the expanding leukemic population and is associated with inferior survival.

Show evidence (4 references)

PMID:39294124 SUPPORT Human Clinical

"We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation..."

Multiomic single-cell profiling of 14 newly diagnosed adult MPAL cases establishes the shared stem-like transcriptional state and links greater differentiation potential to worse survival.

PMID:29991687 SUPPORT Human Clinical

"Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions."

Integrative genomic and methylation analysis ties the epigenetic state of MPAL directly to lineage-commitment gene expression.

PMID:29991687 SUPPORT Human Clinical

"Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given."

Shows the epigenetic lineage class is clinically actionable, supporting it as a real mechanistic layer rather than a descriptive one.

+ 1 more reference

BCR-ABL1 Kinase-Driven Proliferative Signaling

In BCR::ABL1-positive MPAL, the t(9;22) fusion produces a constitutively active ABL1 tyrosine kinase that drives RAS-MAPK and PI3K-AKT signaling independently of physiological growth factors. This supplies the proliferative and survival drive of the clone but does not by itself determine lineage, which is why the same fusion produces CML, Ph-positive B-ALL, or MPAL depending on the compartment in which it is acquired.

ABL1 hgnc:76 BCR hgnc:1014

Ras protein signal transduction GO:0007265 ↑ INCREASED PI3K-AKT signal transduction GO:0043491 ↑ INCREASED

Downstream

Clonal Blast Expansion and Bone Marrow Replacement Constitutive kinase output drives growth-factor-independent expansion of the ambiguous-lineage clone.

Show evidence (2 references)

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

Establishes t(9;22)/BCR::ABL1 as the most frequent recurrent lesion in WHO-defined MPAL, the lesion modelled by this node.

PMID:25605373 SUPPORT Other

"addition of a tyrosine kinase inhibitor in patients with t(9;22) translocation is recommended"

The therapeutic recommendation to add a kinase inhibitor for t(9;22) MPAL reflects the actionable kinase dependency asserted by this node.

KMT2A Rearrangement and Aberrant HOXA Transcriptional Program

Rearrangement of KMT2A at 11q23.3 replaces the wild-type methyltransferase with a fusion that recruits the DOT1L/super-elongation machinery to KMT2A target loci and enforces sustained expression of HOXA cluster genes and MEIS1. This locks the cell in a self-renewing, stem-like state in which lineage commitment cannot proceed, and it also underlies the well-described tendency of KMT2A-rearranged leukemias to switch lineage.

hematopoietic multipotent progenitor cell CL:0000837

KMT2A hgnc:7132 MEN1 hgnc:7010

stem cell differentiation GO:0048863 ⚠ ABNORMAL

Downstream

Failure of Lineage Commitment The KMT2A fusion transcriptional program actively sustains an uncommitted, stem-like state instead of permitting lineage resolution.

Lineage Plasticity and Therapy Escape KMT2A-rearranged clones are the archetype of therapy-associated lineage switch between lymphoid and myeloid phenotypes.

Show evidence (2 references)

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

Documents 11q23/KMT2A rearrangement as a recurrent defining lesion in a WHO-defined MPAL cohort.

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia with BCR::ABL1 fusion Mixed-phenotype acute leukaemia with KMT2A rearrangement"

WHO-HAEM5 elevates KMT2A rearrangement to a defining genetic abnormality of ambiguous-lineage acute leukemia.

ZNF384 Rearrangement and B/Myeloid Programming

Rearrangements that fuse the ZNF384 transcription factor to partners such as TCF3, EP300, CREBBP or TAF15 generate a chimeric transcriptional regulator that imposes a hybrid B-lymphoid/myeloid expression program. ZNF384 fusions are the recurrent alteration most characteristic of B/myeloid MPAL and link that subtype to the ZNF384-rearranged subgroup of B-ALL.

precursor B cell CL:0000817

ZNF384 hgnc:11955

myeloid leukocyte differentiation GO:0002573 ⚠ ABNORMAL

Downstream

Cross-Lineage Antigen Co-expression The chimeric ZNF384 regulator directly drives simultaneous B-lymphoid and myeloid antigen expression in the blast.

Show evidence (5 references)

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Identifies ZNF384 rearrangement as the recurrent lesion of B/myeloid MPAL.

PMID:35732831 SUPPORT Other

"Mixed-phenotype acute leukaemia with ZNF384 rearrangement"

WHO-HAEM5 recognizes ZNF384-rearranged MPAL as a named subtype under ambiguous-lineage leukemia with other defined genetic alterations.

PMID:35247902 SUPPORT Model Organism

"Using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPC) and a Ep300::Znf384 knockin mouse model, we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal."

Provides direct functional evidence that ZNF384 fusion oncoproteins cause myeloid skewing and self-renewal in hematopoietic progenitors.

+ 2 more references

Immature T-Lineage Program with Retained Myeloid Potential

T/myeloid MPAL arises from a thymic-seeding or pre-thymic progenitor that has begun T-lineage specification (cytoplasmic CD3 is expressed) but has not extinguished myeloid potential. The genomic landscape overlaps extensively with early T-cell precursor ALL, with recurrent WT1, PHF6, RUNX1, ETV6 and NOTCH1 alterations and BCL11B enhancer hijacking, placing T/myeloid MPAL and ETP-ALL on a biological continuum.

pro-T cell CL:0000827

WT1 hgnc:12796 PHF6 hgnc:18145 ETV6 hgnc:3495 BCL11B hgnc:13222

T cell differentiation GO:0030217 ⚠ ABNORMAL

Downstream

Cross-Lineage Antigen Co-expression Partial T-lineage specification with retained myeloid competence yields blasts that satisfy both T and myeloid lineage-assignment criteria.

Show evidence (3 references)

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Establishes both the recurrent biallelic WT1 lesion and the genomic continuity between T/myeloid MPAL and early T-cell precursor ALL that this node asserts.

PMID:35732831 SUPPORT Other

"BCL11B rearrangements in MPAL T/ Myeloid, ETP-ALL, acute leukaemia of ambiguous lineage (ALAL) and a subset of AML with minimal differentiation suggests a biologic continuum across these entities"

WHO-HAEM5 states that BCL11B rearrangement links T/myeloid MPAL, ETP-ALL and immature AML in a biologic continuum, supporting both the BCL11B lesion and the ETP-ALL overlap described here.

PMID:37845689 SUPPORT Human Clinical

"Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed that T/My MPAL had greater overlap with ETP-ALL cases."

Single-cell transcriptomics places T/myeloid MPAL closest to ETP-ALL, corroborating the immature-T-with-retained-myeloid-potential model.

Cross-Lineage Antigen Co-expression

The defining, diagnostically operationalized event: blasts express lineage-assigning antigens of more than one lineage, either within a single population (biphenotypic) or as two coexisting populations (bilineal). WHO/ICC criteria assign myeloid lineage on myeloperoxidase expression or monocytic differentiation, T lineage on cytoplasmic or surface CD3, and B lineage on strong CD19 with at least one of CD79a, cytoplasmic CD22 or CD10, or weak CD19 with at least two of these. In acute undifferentiated leukemia the same machinery fails in the opposite direction and no lineage marker is expressed at all.

myeloblast CL:0000835 precursor B cell CL:0000817

MPO hgnc:7218 CD19 hgnc:1633

hemopoiesis GO:0030097 ⚠ ABNORMAL

Downstream

Clonal Blast Expansion and Bone Marrow Replacement Blasts arrested in an ambiguous, non-maturing state accumulate rather than terminally differentiating and dying.

Leukemia Demonstration of cross-lineage antigen co-expression on acute leukemia blasts is what establishes the diagnosis of mixed phenotype acute leukemia.

Show evidence (3 references)

PMID:21228332 SUPPORT Human Clinical

"Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations."

Documents the actual distribution of cross-lineage antigen combinations that define MPAL in a WHO-criteria cohort.

PMID:21228332 SUPPORT Human Clinical

"Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers."

Describes the marker-based lineage-assignment operationalization used to diagnose MPAL.

PMID:35732831 SUPPORT Other

"Myeloperoxidase Intensity in part exceeds 50% of mature neutrophil level"

The WHO-HAEM5 lineage-assignment table gives the quantitative myeloperoxidase threshold used to assign myeloid lineage.

Clonal Blast Expansion and Bone Marrow Replacement

The transformed, maturation-arrested clone expands in the bone marrow, progressively displacing normal hematopoietic elements. Expansion is driven by growth-factor-independent proliferation and impaired apoptosis, and blasts spill into peripheral blood.

hematopoietic multipotent progenitor cell CL:0000837

cell population proliferation GO:0008283 ↑ INCREASED apoptotic process GO:0006915 ↓ DECREASED

Downstream

Bone Marrow Failure and Peripheral Cytopenias Physical and functional displacement of normal hematopoiesis by the expanding blast population.

Extramedullary Leukemic Infiltration Circulating blasts seed liver, spleen, lymph nodes and the central nervous system.

Increased total leukocyte count Egress of blasts from marrow into blood raises the total leukocyte count.

Leukemia Blast expansion in marrow and blood constitutes the acute leukemia itself.

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of hematopoietic malignancies in which blasts show markers of multiple developmental lineages and cannot be clearly classified as acute myeloid or lymphoblastic leukemias."

Establishes MPAL as an acute leukemia driven by an expanding blast population; marked PARTIAL because the quotation characterizes the lineage ambiguity rather than quantifying marrow replacement itself.

Bone Marrow Failure and Peripheral Cytopenias

Replacement of normal marrow by blasts suppresses erythropoiesis, granulopoiesis and megakaryopoiesis, producing the cytopenia triad of anemia, neutropenia and thrombocytopenia that generates most of the presenting clinical features of MPAL.

hematopoietic stem cell CL:0000037

hemopoiesis GO:0030097 ↓ DECREASED

Downstream

Anemia Suppressed erythropoiesis lowers hemoglobin.

Thrombocytopenia Suppressed megakaryopoiesis lowers the platelet count.

Decreased total neutrophil count Suppressed granulopoiesis lowers the neutrophil count.

Fatigue Anemia produces fatigue and exercise intolerance.

Pallor Reduced hemoglobin produces mucocutaneous pallor.

Abnormal bleeding Thrombocytopenia impairs primary hemostasis.

Petechiae Thrombocytopenia produces petechial skin and mucosal bleeding.

Recurrent infections Neutropenia predisposes to bacterial and fungal infection.

Fever Fever arises from neutropenic infection and from cytokine release by the leukemic clone.

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

States that MPAL presents with the anemia, hemorrhage and infection triad, that is, the clinical consequences of marrow-failure cytopenias.

Extramedullary Leukemic Infiltration

Circulating ambiguous-lineage blasts infiltrate reticuloendothelial and sanctuary tissues, producing organomegaly, lymphadenopathy, periosteal bone pain and, in a minority, central nervous system disease that motivates routine CNS-directed prophylaxis.

myeloblast CL:0000835

cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Hepatosplenomegaly Blast infiltration of liver and spleen produces organomegaly.

Lymphadenopathy Nodal blast infiltration produces lymphadenopathy.

Bone pain Marrow packing and periosteal involvement cause bone pain.

Show evidence (1 reference)

PMID:28422191 SUPPORT Human Clinical

"The involvement of the CNS at presentation was noted in 5 (18.5%) cases among 27 children with MPAL diagnosed according to the EGIL criteria and in 2 (18.2%) out of 11 children meeting the 2008 WHO criteria"

Quantifies central nervous system involvement at presentation in pediatric MPAL, an extramedullary infiltration site.

Lineage Plasticity and Therapy Escape

Because alternative lineage programs remain transcriptionally accessible, MPAL clones can shift immunophenotype under therapeutic pressure. This is seen as spontaneous lymphoid-to-myeloid switching at relapse, and as antigen-loss or lineage-switch escape from lineage-directed immunotherapy such as CD19-targeted CAR T cells and blinatumomab. Plasticity is a major reason MPAL responds poorly to single-lineage-directed strategies and a principal driver of its inferior outcome relative to ALL.

hematopoietic multipotent progenitor cell CL:0000837

hematopoietic progenitor cell differentiation GO:0002244 ⚠ ABNORMAL

Downstream

Clonal Blast Expansion and Bone Marrow Replacement A lineage-switched subclone escapes lineage-directed therapy and re-expands, producing refractory or relapsed disease.

Show evidence (3 references)

PMID:39813682 SUPPORT Human Clinical

"Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL ... 10/28 35.7%; P = .0003"

Quantifies post-treatment immunophenotypic (lineage) switching in MPAL at roughly one third of cases (10/28, 35.7%) against 2.5% in AML with a mixed phenotype, directly supporting therapy-associated lineage plasticity. The quotation is elided at the AML-MP arm of the comparison; the square brackets the journal places around the percentage are dropped because the validator treats bracketed spans as editorial insertions.

PMID:37474833 SUPPORT Human Clinical

"Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch."

Whole-genome phylogeny shows a lymphoid-to-myeloid lineage switch under anti-CD19 pressure arises by selection of a pre-existing subclone, the escape mechanism this node describes.

PMID:41063702 SUPPORT Other

"The use of lineage-specific targeted approaches may result in therapeutic pressure and lineage switch in patients with acute leukemia with multi-phenotypic potential."

A 2025 review states the general principle that lineage-directed therapy selects for lineage switch in multi-phenotypic acute leukemia.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Blood 7

Leukemia Leukemia HP:0001909

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of hematopoietic malignancies in which blasts show markers of multiple developmental lineages and cannot be clearly classified as acute myeloid or lymphoblastic leukemias."

Establishes MPAL as an acute leukemia, the defining phenotype of this entry.

Anemia Anemia HP:0001903

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states MPAL presents with the anemia, hemorrhage and infection triad of marrow failure; marked PARTIAL because the quotation groups the cytopenia consequences rather than reporting this individual cytopenia separately.

Thrombocytopenia Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states MPAL presents with the anemia, hemorrhage and infection triad of marrow failure; marked PARTIAL because the quotation groups the cytopenia consequences rather than reporting this individual cytopenia separately.

Decreased total neutrophil count Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states MPAL presents with the anemia, hemorrhage and infection triad of marrow failure; marked PARTIAL because the quotation groups the cytopenia consequences rather than reporting this individual cytopenia separately.

Increased total leukocyte count Increased total leukocyte count HP:0001974

Show evidence (2 references)

PMID:28422191 SUPPORT Other

"Extramedullary involvement (particularly CNS) is report- ed to be more frequent in comparison to ALL or AML. This difference can be partly explained by a relatively higher occurrence of hyperleukocytosis at the diagnosis"

The review states directly that hyperleukocytosis occurs relatively more often at diagnosis in MPAL, and uses it to explain the excess extramedullary involvement. No frequency band is asserted.

PMID:41477275 SUPPORT Other

"Adverse prognostic factors include KMT2Ar, elevated leukocyte counts, extramedullary disease, and bilineage disease biology."

A 2025 MPAL review names elevated leukocyte counts among the recognised adverse prognostic factors, confirming leukocytosis is both a feature and a risk marker of the disease.

Abnormal bleeding Abnormal bleeding HP:0001892

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review names hemorrhage directly among the presenting signs of MPAL. No frequency band is asserted.

Petechiae Petechiae HP:0000967

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review names hemorrhage among the presenting signs of MPAL; petechiae are its characteristic cutaneous form in thrombocytopenic marrow failure. Marked PARTIAL because petechiae are not named separately.

Cardiovascular 2

Hepatosplenomegaly Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"hepatospleno- megaly and lymphadenomegaly were more common in MPAL than in AML"

The review states directly that hepatosplenomegaly is more common in MPAL than in AML. The quotation reproduces the cached line-break hyphenation of "hepatospleno-megaly".

Lymphadenopathy Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"hepatospleno- megaly and lymphadenomegaly were more common in MPAL than in AML"

The review states directly that lymphadenomegaly is more common in MPAL than in AML.

Immune 1

Recurrent infections Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review names infection directly among the presenting signs of MPAL. Marked PARTIAL because the quotation does not establish that the infections are recurrent, and no frequency is asserted.

Integument 1

Pallor Pallor HP:0000980

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states that MPAL patients present with an anemic syndrome, of which mucocutaneous pallor is the cardinal sign. Marked PARTIAL because pallor is not named separately and no frequency is asserted.

Metabolism 1

Fever Fever HP:0001945

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review names infection among the presenting signs of MPAL, the usual proximate cause of fever at diagnosis. Marked PARTIAL because fever itself is not named and no frequency is asserted.

Constitutional 2

Fatigue Fatigue HP:0012378

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states that MPAL patients present with an anemic syndrome; fatigue is the symptomatic expression of that anemia. Marked PARTIAL because fatigue is not named separately and no frequency is asserted.

Bone pain Bone pain HP:0002653

Show evidence (1 reference)

PMID:28422191 PARTIAL Other

"The signs of MPAL patients are similar to those seen in patients with other types of AL, including anemic syn- drome, hemorrhage and infection"

The review states that MPAL presents with the same marrow-failure signs as other acute leukemias, of which bone pain from marrow expansion is one. Marked PARTIAL because bone pain is not named in the quotation and no frequency is asserted.

🧬

Genetic Associations

8

BCR::ABL1

Gene: ABL1 hgnc:76 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

Quantifies t(9;22)/Philadelphia-chromosome frequency at 20% of the 100-patient WHO-2008 reference series.

PMID:32419244 SUPPORT Human Clinical

"On multivariate analyses and after adjustment for age, year of diagnosis and chemotherapy status, Ph+ MPAL patients had reduced risk of death in comparison to Ph(-) MPAL patients"

SEER registry analysis establishes BCR::ABL1/Philadelphia-chromosome status as a prognostically decisive somatic driver in MPAL.

KMT2A rearrangement

Gene: KMT2A hgnc:7132 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:21228332 SUPPORT Human Clinical

"Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes."

Quantifies 11q23/KMT2A rearrangement frequency at 8% of the WHO-2008 reference series.

PMID:32419244 SUPPORT Human Clinical

"So, MLL+ MPAL had the worst outcome with a 10-fold increased risk of death in comparison to Ph+ MPAL patients (HR = 10.2, P < .001)."

Establishes KMT2A/MLL rearrangement as the most adverse prognostic somatic driver in MPAL.

ZNF384 rearrangement

Gene: ZNF384 hgnc:11955 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Landmark genomics establishes ZNF384 rearrangement as the characteristic somatic driver of B/myeloid MPAL.

PMID:35732831 SUPPORT Other

"The ﬁrst subtype is MPAL with ZNF384 rearrangement, which commonly has a B/myeloid immunophenotype and is identiﬁed in ~50% of pediatric B/myeloid MPAL with fusion partners including TCF3, EP300, TAF15, and CREBBP."

WHO-HAEM5 recognizes ZNF384-rearranged MPAL as a named subtype, gives its B/myeloid immunophenotype, its ~50% share of pediatric B/myeloid MPAL, and its fusion partners.

WT1

Gene: WT1 hgnc:12796 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:30209392 SUPPORT Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Landmark genomics establishes biallelic WT1 alteration as characteristic of T/myeloid MPAL.

PHF6

Gene: PHF6 hgnc:18145 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35732831 SUPPORT Other

"Other genomic ﬁndings such as PHF6 mutations and PICALM::"

WHO-HAEM5 lists PHF6 mutation among the genomic findings enriched in MPAL that are not yet subtype-defining. The quoted span stops at the PICALM::MLLT10 fusion name because the cached text breaks that symbol across a line.

RUNX1

Gene: RUNX1 hgnc:10471 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:30209392 PARTIAL Human Clinical

"Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct."

The landmark genomic survey that catalogued the recurrent transcription-factor lesions of MPAL, RUNX1 among them. Support is PARTIAL because the abstract names only ZNF384 and WT1 explicitly; the RUNX1 finding is in the paper body.

NOTCH1

Gene: NOTCH1 hgnc:7881 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:30209392 PARTIAL Human Clinical

"Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia."

Establishes that T/myeloid MPAL shares its genomic landscape with early T-cell precursor ALL, the context for its NOTCH1 lesions. Support is PARTIAL because NOTCH1 is named in the paper body rather than the abstract.

BCL11B

Gene: BCL11B hgnc:13222 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35732831 SUPPORT Other

"The other subtype is ALAL with BCL11B rearrangement, which has a more heterogenous immunophenotype ... in acute undifferentiated leukaemia (AUL) and ~20-30% of T/myeloid MPAL."

WHO-HAEM5 establishes BCL11B rearrangement as a defined ambiguous-lineage subtype and quantifies its share of T/myeloid MPAL at 20-30%.

💊

Medical Actions

9

ALL-Type Induction Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Agent: vincristine CHEBI:28445 dexamethasone CHEBI:41879 daunorubicin CHEBI:41977 asparaginase NCIT:C286

Multi-agent lymphoid-type induction (vincristine, corticosteroid, anthracycline, asparaginase backbone) is the preferred initial regimen for most MPAL, with retrospective and registry data favouring ALL-directed over AML-directed induction for remission rates.

Mechanism Target:

INHIBITS Clonal Blast Expansion and Bone Marrow Replacement

Show evidence (5 references)

PMID:29550836 SUPPORT Human Clinical

"Using either definition of MPAL, ALL-therapy is associated with higher initial remission rates for MPAL and is at least equivalent to more intensive AML therapy for long-term survival."

Systematic review and meta-analysis of 1,499 patients supports ALL-type induction as the preferred initial regimen.

PMID:21228332 SUPPORT Human Clinical

"ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy."

Direct comparison in a WHO-defined cohort shows markedly higher response to ALL-type than AML-type induction.

PMID:31661160 SUPPORT Human Clinical

"The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy."

The Children's Oncology Group task force concludes ALL-type chemotherapy is the preferred initial approach in pediatric MPAL.

+ 2 more references

BCR::ABL1 Tyrosine Kinase Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Imatinib or a second/third-generation tyrosine kinase inhibitor added to chemotherapy for BCR::ABL1-positive MPAL, targeting the constitutively active fusion kinase.

Mechanism Target:

INHIBITS BCR-ABL1 Kinase-Driven Proliferative Signaling

Show evidence (2 references)

PMID:25605373 SUPPORT Other

"addition of a tyrosine kinase inhibitor in patients with t(9;22) translocation is recommended"

Expert treatment guidance recommends adding a TKI for t(9;22)-positive MPAL.

PMID:41063702 SUPPORT Other

"of tyrosine kinase inhibitors for Philadelphia chromosome- positive MPAL) over acute myeloid leukemia or hybrid approaches."

A 2025 review reiterates ALL-directed therapy with a TKI for Philadelphia-positive MPAL over AML-type or hybrid approaches.

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic hematopoietic stem cell transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Consolidation with allogeneic transplant in first complete remission is widely used in MPAL given its inferior outcome relative to ALL, although the benefit is derived from retrospective series rather than randomized trials.

Mechanism Target:

INHIBITS Clonal Blast Expansion and Bone Marrow Replacement

Show evidence (4 references)

PMID:28099272 SUPPORT Other

"Allogeneic transplantation in first remission may be associated with improved survival compared with consolidation chemotherapy."

Supports allogeneic transplant in first remission as a consolidation strategy in MPAL.

PMID:25605373 SUPPORT Other

"The limited available data suggest that an "acute lymphoblastic leukemia-like" regimen followed by allogeneic stem-cell transplant may be advisable"

Expert guidance places allogeneic transplant after ALL-type induction in adult MPAL.

PMID:32060402 PARTIAL Human Clinical

"In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients."

Qualifies the transplant recommendation: in children who clear MRD, transplantation was not required, so this evidence partially refutes a universal transplant-in-CR1 policy while supporting it for adults.

+ 1 more reference

Central Nervous System-Directed Prophylaxis

Action: intrathecal chemotherapy Ontology label: Intrathecal Chemotherapy NCIT:C15750

Intrathecal chemotherapy is given as CNS prophylaxis following ALL-type protocols, because MPAL carries a meaningful risk of central nervous system involvement.

Mechanism Target:

INHIBITS Extramedullary Leukemic Infiltration

Show evidence (1 reference)

PMID:28422191 SUPPORT Other

"intrathecal chemotherapy should be supplemented by prophylactic irradiation of the CNS"

The review describes intrathecal chemotherapy as the CNS-directed prophylaxis backbone in MPAL, intensified with cranial irradiation in high-white-count or Philadelphia-positive disease.

Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Transfusion support, antimicrobial prophylaxis and management of tumor lysis syndrome address the consequences of marrow failure and of cytoreduction.

Mechanism Target:

MODULATES Bone Marrow Failure and Peripheral Cytopenias

Blinatumomab (CD19-Directed T-Cell Engager)

Action: Pharmacotherapy NCIT:C15986

Agent: blinatumomab NCIT:C62528

The CD19/CD3 bispecific T-cell engager blinatumomab is used in CD19-positive MPAL, principally in relapsed or refractory disease, in measurable-residual-disease-positive remission, and in KMT2A-rearranged infant protocols. Because it applies lineage-specific selective pressure, it carries a documented risk of antigen-loss or lineage-switch escape, so response should be monitored with lineage-aware measurable residual disease assessment.

Mechanism Target:

INHIBITS Cross-Lineage Antigen Co-expression — Targets the B-lineage antigen CD19 expressed by the cross-lineage blast population.

Show evidence (2 references)

PMID:41063702 PARTIAL Other

"The use of lineage-specific targeted approaches may result in therapeutic pressure and lineage switch in patients with acute leukemia with multi-phenotypic potential."

Supports use of lineage-specific targeted agents in ambiguous-lineage leukemia while documenting their principal liability; marked PARTIAL because the quotation states the risk rather than establishing efficacy.

PMID:37474833 REFUTE Human Clinical

"Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML)."

Documents the failure mode of CD19-directed therapy in lineage-plastic leukemia, refuting any assumption of durable lineage-restricted control.

CD19-Directed CAR T-Cell Therapy

Action: chimeric antigen receptor T-cell therapy Ontology label: Chimeric Antigen Receptor T-Cell Therapy NCIT:C126102

Autologous CD19-directed chimeric antigen receptor T cells are used off-label in CD19-positive relapsed or refractory MPAL, with the evidence base limited to case reports and small series extrapolated from B-ALL. Curated separately from blinatumomab because it is a distinct therapeutic modality (an engineered cell product rather than an antibody construct), even though the two share the CD19 target and the same lineage-switch escape liability.

Mechanism Target:

INHIBITS Cross-Lineage Antigen Co-expression — Redirected T cells lyse blasts bearing the B-lineage antigen CD19 within the cross-lineage blast population.

Show evidence (2 references)

PMID:37474833 PARTIAL Human Clinical

"Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML)."

Establishes that anti-CD19 cellular therapy is given in this setting while documenting its lineage-switch failure mode; PARTIAL because the report addresses escape rather than efficacy in MPAL.

PMID:41063702 PARTIAL Other

"The use of lineage-specific targeted approaches may result in therapeutic pressure and lineage switch in patients with acute leukemia with multi-phenotypic potential."

A 2025 review of ambiguous-lineage leukemia frames lineage-directed cellular and antibody therapy as usable but escape-prone; PARTIAL because it states the liability rather than establishing efficacy.

BCL-2 Inhibition with Venetoclax

Action: Pharmacotherapy NCIT:C15986

Agent: venetoclax CHEBI:133021 azacitidine CHEBI:2038

Investigational in MPAL. Venetoclax combined with a hypomethylating agent is a lineage-agnostic, BCL-2-directed regimen now being tested prospectively in newly diagnosed MPAL, with treatment stratified by B/myeloid versus T/myeloid immunophenotype. No randomized efficacy data exist in MPAL and use outside trials is extrapolated from AML.

Mechanism Target:

INHIBITS Clonal Blast Expansion and Bone Marrow Replacement — BCL-2 inhibition restores the apoptotic threshold of the maturation-arrested blast, a lineage-agnostic target that does not depend on which lineage the blast is expressing.

Show evidence (2 references)

clinicaltrials:NCT07573670 PARTIAL Human Clinical

"Eligible subjects are divided into two cohorts based on immunophenotype: Cohort A (T/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine, and Cohort B (B/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine + blinatumomab."

A prospective MPAL-specific phase 2 study of BCL-2 inhibition plus azacitidine; PARTIAL because the trial is ongoing and no efficacy results are yet reported, and because the registration record names only "Bcl-2 Inhibitor" rather than a specific agent, so this record alone does not source the venetoclax identity of the CHEBI binding.

PMID:41540127 PARTIAL Human Clinical

"who received induction therapy with the mini-CVD regimen (cyclophosphamide, vincristine, dexamethasone) combined with venetoclax and azacitidine ... Among this cohort, 92.3% of patients (12/13) achieved complete remission (CR)."

Names venetoclax and azacitidine explicitly as the BCL-2-directed combination actually given in acute leukemia of ambiguous lineage, which is what sources the CHEBI:133021 / CHEBI:2038 agent bindings that the trial record leaves as a generic drug class. PARTIAL rather than SUPPORT: this is a single-center retrospective series of 13 Philadelphia-negative ALAL patients, venetoclax and azacitidine were given on a mini-CVD backbone rather than as the doublet the trial is testing, and the cohort is ALAL rather than MPAL-restricted, so it establishes the agent identity and clinical plausibility but not efficacy of the regimen in MPAL.

FLT3 Inhibition in ZNF384-Rearranged Disease

Action: Pharmacotherapy NCIT:C15986

Agent: gilteritinib NCIT:C116722

Investigational only. Preclinical work in ZNF384-rearranged leukemia identified FLT3 as a dependency, with in vivo response of a ZNF384-rearranged xenograft to FLT3 inhibition. No clinical efficacy has been established in MPAL.

Mechanism Target:

INHIBITS ZNF384 Rearrangement and B/Myeloid Programming — Targets the FLT3 dependency created by the ZNF384 fusion transcriptional program.

Show evidence (1 reference)

PMID:35247902 SUPPORT Model Organism

"In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged xenograft to FLT3 inhibition in vivo."

Xenograft evidence for FLT3 inhibitor sensitivity in ZNF384-rearranged leukemia; preclinical only, and it does not establish clinical benefit in MPAL.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Mixed Phenotype Acute Leukemia:

Acute myeloid leukemia with aberrant lymphoid antigen expression MONDO:0018874

Overlapping Features AML blasts frequently express individual lymphoid antigens such as CD7 or CD19 without meeting formal lineage-assignment thresholds; this is aberrant antigen expression, not MPAL.

Distinguishing Features

MPAL requires formal WHO/ICC lineage-assignment criteria for two lineages
single aberrant antigens without cytoplasmic CD3 or CD19-anchored combinations do not assign a second lineage

Show evidence (1 reference)

PMID:35732831 PARTIAL Other

"Myeloperoxidase Intensity in part exceeds 50% of mature neutrophil level"

WHO-HAEM5 sets a quantitative intensity threshold for lineage assignment, which is what separates true MPAL from AML carrying sub-threshold aberrant lymphoid antigens; PARTIAL because the quoted row gives the myeloid threshold rather than the full rule set.

Early T-cell precursor acute lymphoblastic leukemia Not Yet Curated MONDO:0100291

Overlapping Features ETP-ALL shares an immature immunophenotype, myeloid/stem antigen expression and much of its genomic landscape with T/myeloid MPAL.

Distinguishing Features

ETP-ALL is myeloperoxidase-negative by definition
T/myeloid MPAL satisfies myeloid lineage assignment, usually via myeloperoxidase

Show evidence (1 reference)

PMID:37845689 SUPPORT Human Clinical

"Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed that T/My MPAL had greater overlap with ETP-ALL cases."

Quantifies the transcriptional proximity of T/myeloid MPAL to ETP-ALL, which is why ETP-ALL is the principal differential for this subtype.

Acute undifferentiated leukemia Not Yet Curated MONDO:0020321

Overlapping Features AUL blasts express no lineage-defining marker at all rather than more than one.

Distinguishing Features

AUL assigns no lineage; MPAL assigns two or more

Show evidence (1 reference)

PMID:31982153 SUPPORT Human Clinical

"Acute undifferentiated leukemia (AUL) is rare and defined by the absence of bona fide myeloid and lymphoid markers."

Defines AUL by absence of lineage-defining markers, the exact inverse of the MPAL requirement that two or more lineages be assigned.

Acute lymphoblastic leukemia MONDO:0004967

Overlapping Features Lineage-committed B-ALL or T-ALL without qualifying cross-lineage myeloid antigen expression.

Distinguishing Features

absence of myeloperoxidase or monocytic differentiation markers

Blastic plasmacytoid dendritic cell neoplasm Not Yet Curated MONDO:0019467

Overlapping Features An immature CD4+/CD56+/CD123+ neoplasm that can mimic ambiguous-lineage leukemia.

Distinguishing Features

characteristic CD123/TCL1/CD303 profile without myeloid or lymphoid lineage assignment

Acute myeloid leukemia with a mixed phenotype MONDO:0018874

Overlapping Features Acute myeloid leukemia that displays a mixed immunophenotype but is biologically and clinically distinct from de novo MPAL, with more frequent RUNX1 and TP53 mutations, inferior response, and little capacity for post-treatment lineage switch. Recognizing it matters because it responds poorly to the ALL-directed induction that benefits true MPAL.

Distinguishing Features

enrichment for RUNX1 and TP53 driver mutations
inferior response to induction
rarely switches to a lymphoid immunophenotype after treatment

Show evidence (2 references)

PMID:39813682 SUPPORT Human Clinical

"and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation."

Genomic and transcriptomic separation of AML with mixed phenotype from MPAL, the basis for treating them as distinct diagnoses.

PMID:39813682 SUPPORT Human Clinical

"AML-MP has inferior responses (hazard ratio, 12.5; 95% confidence interval, 2.72-57.8; P = .001), whereas MPAL has better responses to ALL-directed treatment."

Establishes the clinical consequence of the distinction: ALL-directed therapy benefits MPAL but not AML with a mixed phenotype.

Acute myeloid leukemia with defining recurrent genetic abnormalities MONDO:0018874

Overlapping Features A leukemia carrying an AML-defining lesion such as t(8;21)/RUNX1::RUNX1T1, inv(16)/CBFB::MYH11 or t(15;17)/PML::RARA is classified as that AML entity even if the blasts show a mixed immunophenotype, and is excluded from MPAL by WHO and ICC convention. Note that MONDO's umbrella term for this WHO grouping (MONDO:0020078, "acute myeloid leukemia with recurrent genetic anomaly") is obsolete and the individual lesion-specific children are too narrow to stand for the grouping, so the differential is anchored on the parent MONDO:0018874 with a more specific preferred_term.

Distinguishing Features

presence of an AML-defining recurrent genetic abnormality overrides the mixed immunophenotype

🔬

Clinical Trials

4

NCT05327894 PHASE_III RECRUITING

Interfant-21, an international collaborative treatment protocol adding blinatumomab for infants under one year with KMT2A-rearranged acute lymphoblastic leukemia or mixed phenotype acute leukemia.

Target Phenotypes: Leukemia HP:0001909

Show evidence (1 reference)

clinicaltrials:NCT05327894 SUPPORT Human Clinical

"This study is a treatment protocol with blinatumomab for infants under 1 year old who are diagnosed with acute lymphoblastic leukemia with a specific unfavorable genetic alteration."

Interfant-21 enrolls infants with KMT2A-rearranged MPAL alongside KMT2A-rearranged ALL, reflecting the shared KMT2A biology curated here.

NCT04872478 PHASE_I RECRUITING

Dose-escalation study of the oral MERTK/FLT3 inhibitor MRX-2843 in adolescents and adults with relapsed or refractory AML, ALL, or mixed phenotype acute leukemia.

Target Phenotypes: Leukemia HP:0001909

Show evidence (1 reference)

clinicaltrials:NCT04872478 SUPPORT Human Clinical

"This is a Phase I, open-label, non-randomized, dose escalation study in adolescents and adults with relapsed/refractory acute myeloid leukemia, acute lymphoblastic leukemia, or mixed phenotype acute leukemia."

An early-phase trial explicitly enrolling relapsed/refractory MPAL, illustrating the kinase-inhibitor strategy in ambiguous-lineage disease.

NCT07573670 PHASE_II NOT_RECRUITING

Two-cohort phase 2 study of a BCL-2 inhibitor plus azacitidine in newly diagnosed MPAL, with blinatumomab added for the B/myeloid cohort and allogeneic transplant planned for responders. One of the first prospective, immunophenotype-stratified, MPAL-specific treatment trials, directly addressing the open induction question curated here.

Target Phenotypes: Leukemia HP:0001909

Show evidence (1 reference)

clinicaltrials:NCT07573670 SUPPORT Human Clinical

"Eligible subjects are divided into two cohorts based on immunophenotype: Cohort A (T/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine, and Cohort B (B/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine + blinatumomab."

A prospective MPAL-specific trial that stratifies treatment by B/myeloid versus T/myeloid immunophenotype, testing exactly the phenotype-directed approach this entry records as unresolved.

NCT07222579 PHASE_II RECRUITING

Multicenter phase 2 study of subcutaneous blinatumomab in adults with CD19-positive MPAL across three cohorts: unfit newly diagnosed disease, MRD-positive remission, and morphologic relapsed/refractory disease. The most direct prospective test of CD19-directed immunotherapy in MPAL.

Target Phenotypes: Leukemia HP:0001909

Show evidence (1 reference)

clinicaltrials:NCT07222579 SUPPORT Human Clinical

"This is a multicenter, non-randomized, open-label, phase II study evaluating blinatumomab administered subcutaneously in adult subjects with CD19+ MPAL."

An active MPAL-specific phase 2 trial of CD19-directed bispecific therapy, the investigational context for the CD19-Directed Immunotherapy treatment entry and for the lineage-escape risk recorded on the plasticity node.

{ }

Source YAML

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name: Mixed Phenotype Acute Leukemia
creation_date: '2026-07-31T00:00:00Z'
description: >-
  Mixed phenotype acute leukemia (MPAL) is an acute leukemia of ambiguous
  lineage in which the blast population cannot be assigned to a single
  hematopoietic lineage. Blasts either co-express lineage-defining myeloid
  and lymphoid (B or T) antigens within one population (the historical
  "biphenotypic" pattern) or form two separate lineage-committed populations
  (the "bilineal" pattern). MPAL accounts for a small minority of acute
  leukemias, arises from transformation of an immature multipotent
  hematopoietic progenitor that retains lineage plasticity, and is defined
  operationally by WHO/ICC immunophenotypic lineage-assignment criteria
  (myeloperoxidase or monocytic markers for myeloid lineage, cytoplasmic
  CD3 for T lineage, and CD19-anchored marker combinations for B lineage).
  Current classifications recognize genetically defined subtypes (BCR::ABL1,
  KMT2A rearrangement), immunophenotypically defined not-otherwise-specified
  subtypes (B/myeloid, T/myeloid), and the related fully undifferentiated
  entity acute undifferentiated leukemia.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Acute Leukemia of Ambiguous Lineage
parents:
- acute leukemia of ambiguous lineage
disease_term:
  preferred_term: mixed phenotype acute leukemia
  term:
    id: MONDO:0020743
    label: mixed phenotype acute leukemia
synonyms:
- MPAL
- acute biphenotypic leukemia
- acute bilineal leukemia
- acute leukemia of ambiguous lineage
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0020322
      label: acute biphenotypic leukemia
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0020322 (acute biphenotypic leukemia) is the narrower WHO-2001-era
      term for the single-blast-population co-expression pattern and is a
      subclass of MONDO:0020743. Issue #7468 cited MONDO:0020322, but this
      entry is scoped to the full WHO/ICC mixed phenotype acute leukemia
      family, which also includes the bilineal (two separate blast
      populations) pattern, so MONDO:0020743 is used as the primary term.
  - term:
      id: MONDO:0019460
      label: acute leukemia of ambiguous lineage
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      The parent category that additionally contains acute undifferentiated
      leukemia, which is curated here as a related ambiguous-lineage subtype.
has_subtypes:
- name: MPAL BCR-ABL1
  display_name: Mixed phenotype acute leukemia with BCR::ABL1 fusion
  classification: genetically defined
  description: >-
    MPAL carrying t(9;22)(q34.1;q11.2) / BCR::ABL1. Recognized as a distinct
    WHO/ICC entity because the fusion kinase supplies a targetable signaling
    dependency, and tyrosine kinase inhibitors are added to the treatment
    backbone.
  subtype_term:
    preferred_term: mixed phenotype acute leukemia with BCR-ABL1
    term:
      id: MONDO:0850449
      label: mixed phenotype acute leukemia with BCR-ABL1
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia with BCR::ABL1 fusion
      Mixed-phenotype acute leukaemia with KMT2A rearrangement
    explanation: >-
      WHO-HAEM5 lists MPAL with BCR::ABL1 fusion as one of the two
      genetically defined ambiguous-lineage entities.
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      In a 100-patient WHO-defined MPAL series t(9;22) was the single most
      common recurrent lesion, supporting it as a defined subtype.
- name: MPAL KMT2A
  display_name: Mixed phenotype acute leukemia with KMT2A rearrangement
  classification: genetically defined
  description: >-
    MPAL carrying a rearrangement of KMT2A (MLL) at 11q23.3, most often with a
    B/myeloid immunophenotype. KMT2A fusions enforce an aberrant HOXA/MEIS1
    transcriptional program in an immature progenitor, and this subtype is
    over-represented in infants.
  subtype_term:
    preferred_term: mixed phenotype acute leukemia with MLL rearranged
    term:
      id: MONDO:0850450
      label: mixed phenotype acute leukemia with MLL rearranged
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia with BCR::ABL1 fusion
      Mixed-phenotype acute leukaemia with KMT2A rearrangement
    explanation: >-
      WHO-HAEM5 lists MPAL with KMT2A rearrangement as the second genetically
      defined ambiguous-lineage entity.
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      11q23/KMT2A rearrangements were the second most common recurrent
      cytogenetic lesion in this WHO-defined MPAL series.
- name: MPAL B/myeloid NOS
  display_name: Mixed phenotype acute leukemia, B/myeloid, not otherwise specified
  classification: immunophenotypically defined
  description: >-
    MPAL meeting WHO/ICC criteria for both B and myeloid lineage assignment
    without a defining BCR::ABL1 or KMT2A lesion. ZNF384 rearrangements are
    the most characteristic recurrent alteration in this group.
  subtype_term:
    preferred_term: mixed phenotype acute leukemia, B/myeloid
    term:
      id: MONDO:0850451
      label: mixed phenotype acute leukemia, B/myeloid
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia, B/myeloid
      Mixed-phenotype acute leukaemia, T/myeloid
      Mixed-phenotype acute leukaemia, rare types
    explanation: >-
      WHO-HAEM5 defines B/myeloid MPAL as one of the immunophenotypically
      defined ambiguous-lineage entities.
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Genomic profiling establishes ZNF384 rearrangement as the recurrent
      lesion characteristic of B/myeloid MPAL.
- name: MPAL T/myeloid NOS
  display_name: Mixed phenotype acute leukemia, T/myeloid, not otherwise specified
  classification: immunophenotypically defined
  description: >-
    MPAL meeting WHO/ICC criteria for both T and myeloid lineage assignment
    without a defining genetic lesion. Genomically it overlaps substantially
    with early T-cell precursor ALL, with recurrent WT1, PHF6, RUNX1, ETV6 and
    NOTCH1 alterations and frequent BCL11B enhancer hijacking.
  subtype_term:
    preferred_term: mixed phenotype acute leukemia, T/myeloid
    term:
      id: MONDO:0850452
      label: mixed phenotype acute leukemia,T/myeloid
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia, B/myeloid
      Mixed-phenotype acute leukaemia, T/myeloid
      Mixed-phenotype acute leukaemia, rare types
    explanation: >-
      WHO-HAEM5 defines T/myeloid MPAL as an immunophenotypically defined
      ambiguous-lineage entity.
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Genomic profiling shows T/myeloid MPAL is defined by biallelic WT1
      alterations and overlaps early T-cell precursor ALL.
- name: ALAL BCL11B
  display_name: Acute leukemia of ambiguous lineage with BCL11B rearrangement
  classification: genetically defined
  description: >-
    Ambiguous-lineage acute leukemia carrying a structural rearrangement that
    hijacks an enhancer to BCL11B at 14q32.2. WHO-HAEM5 and the ICC name it as
    a defined ambiguous-lineage genetic group alongside ZNF384-rearranged
    disease. It is curated at subtype level rather than folded into the
    T/myeloid NOS group because the entity spans acute undifferentiated
    leukemia and T/myeloid MPAL, and reaches into ETP-ALL and AML with minimal
    differentiation, so it cuts across the immunophenotypically defined
    subtypes rather than sitting inside one. No MONDO term exists for this
    entity yet, so no subtype_term is bound.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The other subtype is ALAL with BCL11B rearrangement, which has a more
      heterogenous immunophenotype ... in acute undifferentiated
      leukaemia (AUL) and ~20-30% of T/myeloid MPAL.
    explanation: >-
      WHO-HAEM5 names ALAL with BCL11B rearrangement as a defined
      ambiguous-lineage subtype and gives its 20-30% share of T/myeloid MPAL
      and its overlap with acute undifferentiated leukemia.
  - reference: PMID:41477275
    reference_title: Mixed phenotype acute leukemia, the dissection of an enigmatic disease in the era of novel therapies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with specific subcategories characterized by
      BCR::ABL1, KMT2A, ZNF384, or BCL11B rearrangements.
    explanation: >-
      A 2025 review lists BCL11B rearrangement among the four genetic
      subcategories of MPAL, alongside BCR::ABL1, KMT2A and ZNF384.
- name: Acute undifferentiated leukemia
  display_name: Acute undifferentiated leukemia (AUL)
  classification: related ambiguous-lineage entity
  description: >-
    An acute leukemia of ambiguous lineage in which blasts express no
    lineage-defining marker at all (no myeloperoxidase, no cytoplasmic CD3, no
    B-lineage marker combination) and typically carry only immaturity markers
    such as CD34, HLA-DR and TdT. AUL is not strictly MPAL, since no lineage
    is assigned rather than more than one, but it sits in the same
    ambiguous-lineage category and shares the immature-progenitor cell of
    origin, so it is curated here as a related subtype.
  subtype_term:
    preferred_term: acute undifferentiated leukemia
    term:
      id: MONDO:0020321
      label: acute undifferentiated leukemia
  evidence:
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute undifferentiated leukemia (AUL) is rare and defined by the absence
      of bona fide myeloid and lymphoid markers.
    explanation: >-
      Defines AUL by absence of lineage-defining markers, contrasting with
      MPAL where more than one lineage is assigned.
epidemiology:
- name: Share of acute leukemias
  description: >-
    MPAL is a small minority of acute leukemias. Reported shares range from
    about 1% to 5% and vary with the classification criteria used (EGIL,
    WHO2008, WHO2016, WHO-HAEM5/ICC), since successive revisions have
    tightened the marker requirements and moved some formerly biphenotypic
    cases into other entities.
  minimum_value: 1.0
  maximum_value: 5.0
  unit: percent of acute leukemias
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Historically, various names and classifications were used for this rare
      entity accounting for 2-5% of all acute leukemias depending on the
      diagnostic criterias used.
    explanation: >-
      Gives the 2-5% share and explicitly attributes the range to differing
      diagnostic criteria.
  - reference: PMID:31661160
    reference_title: "Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mixed phenotype acute leukemia (MPAL) is uncommon, comprising 1–5% of
      newly diagnosed acute leukemia.
    explanation: >-
      The Children's Oncology Group task force cites the wider 1-5% range,
      which is the interval recorded here.
  - reference: PMID:29991687
    reference_title: Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Such types of acute leukemia are classified as mixed phenotype acute
      leukemia (MPAL), which accounts for 1–3% of acute leukemias in adults
    explanation: >-
      Reports the narrower adult-specific share, showing the estimate is
      age-group dependent.
- name: Immunophenotypic subtype distribution
  description: >-
    Across WHO-defined cohorts B/myeloid is the most common combination,
    followed by T/myeloid; B/T and trilineage cases are rare.
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T
      (4%), or trilineage (2%) combinations.
    explanation: >-
      Gives the subtype distribution in a 100-patient WHO-criteria cohort.
  - reference: PMID:37116143
    reference_title: Clinical and Molecular Characteristics of Patients with Mixed Phenotype Acute Leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children represented 49.3% of MPAL patients. The main phenotype was
      B-lymphoid/myeloid (80%).
    explanation: >-
      An independent 75-patient prospective series confirms B/myeloid as the
      predominant immunophenotype.
- name: Age distribution
  description: >-
    MPAL occurs across the age range, with a majority of cases in adults in
    referral series. Acute undifferentiated leukemia by contrast is a disease
    of older adults.
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were 62 men and 38 women; 68% were adults.
    explanation: >-
      Documents adult predominance and male excess in a WHO-defined MPAL
      series.
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to other acute leukemias, patients with AUL have the highest
      median age (74 years); in contrast to acute myeloid leukemia (AML, 65)
      and acute lymphoblastic leukemia (ALL, 12).
    explanation: >-
      Establishes the markedly older age distribution of acute undifferentiated
      leukemia relative to AML and ALL.
prevalence:
- subtype: Acute undifferentiated leukemia
  population: United States (SEER, 2000-2016)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.134
  notes: >-
    1.34 cases per million person-years, converted to 0.134 per 100,000. This
    is the SEER incidence of acute undifferentiated leukemia specifically, the
    only ambiguous-lineage entity for which a population-based rate was
    located; no equivalent population rate for MPAL as a whole was found.
  evidence:
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 1,888 cases of AUL were diagnosed (1.34 per million
      person-years).
    explanation: >-
      Population-based SEER incidence of acute undifferentiated leukemia.
progression:
- phase: Outcome in adult and mixed-age WHO-defined cohorts
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall median survival was 18 months and 37% of patients are alive at 5
      years. Age, Ph(+), and AML therapy were predictors for poor outcome
    explanation: >-
      Provides overall survival and adverse prognostic factors in a
      predominantly adult WHO-defined MPAL cohort.
  notes: >-
    MPAL is a poor-risk acute leukemia; older age, Philadelphia positivity in
    the pre-TKI era, and AML-directed induction were adverse in this series.
- phase: Outcome after allogeneic transplantation in adults
  age_range: adult
  evidence:
  - reference: PMID:36959485
    reference_title: "Multicenter retrospective analysis of clinical outcome of adult patients with mixed-phenotype acute leukemia treated with acute myeloid leukemia-like or acute lymphoblastic leukemia-like chemotherapy and impact of allogeneic stem cell transplantation: a Campus ALL study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An AlloSCT was performed in 50 patients (65%). The 5-year OS of
      transplanted patients was 54%. The OS post-AlloSCT was better in patients
      who were minimal residual disease (MRD)-negative prior to transplant
      (75.8% vs 45.2%, P = 0.06).
    explanation: >-
      Adult transplant outcomes and the dependence of post-transplant survival
      on pre-transplant measurable residual disease status.
  notes: >-
    Adult outcomes have improved relative to older series (median overall
    survival 41.9 months in this cohort), and pre-transplant MRD status is the
    dominant modifier of post-transplant survival.
- phase: Outcome in centrally reviewed pediatric cohorts
  age_range: pediatric
  evidence:
  - reference: PMID:31661160
    reference_title: "Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EFS and OS were 75% ± 13% and
      84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT
    explanation: >-
      Children treated with ALL chemotherapy alone had favourable 5-year
      event-free and overall survival, markedly better than historical adult
      MPAL outcomes.
  notes: >-
    Pediatric MPAL treated on ALL regimens has substantially better outcomes
    than adult disease; selection bias limits causal interpretation of the
    no-transplant subgroup.
- phase: Measurable residual disease response after induction
  evidence:
  - reference: PMID:32060402
    reference_title: "Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in
      most patients (70%). EOI MRD positivity was predictive of 5-year EFS
      (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003).
    explanation: >-
      End-of-induction measurable residual disease is the dominant early
      prognostic variable in pediatric MPAL.
  notes: >-
    Earlier MRD clearance is associated with better survival; MRD is the
    principal proposed variable for therapy adaptation.
- phase: Outcome in acute undifferentiated leukemia
  subtype: Acute undifferentiated leukemia
  evidence:
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among adults, AUL patients had the worst prognosis, with a median overall
      survival (OS) of 9 months, compared to 27 months in ALL and 13 months in
      AML.
    explanation: >-
      AUL has the worst adult survival among the acute leukemias in
      population-based data.
pathophysiology:
- name: Transformation of an Immature Multipotent Hematopoietic Progenitor
  biological_scale: CELLULAR
  description: >-
    MPAL originates in a hematopoietic stem or multipotent progenitor cell
    that has not yet committed to a single lineage. Because the cell of origin
    sits upstream of the myeloid/lymphoid branch point, the founding clone
    retains access to more than one differentiation program, which is the
    structural precondition for the ambiguous phenotype that defines the
    disease.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: hematopoietic progenitor cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0002244
      label: hematopoietic progenitor cell differentiation
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that the intratumoral immunophenotypic heterogeneity
      characteristic of MPAL is independent of somatic genetic variation, that
      founding lesions arise in primitive haematopoietic progenitors, and that
      individual phenotypic subpopulations can reconstitute the immunophenotypic
      diversity in vivo.
    explanation: >-
      Localizes the founding lesions of MPAL to primitive hematopoietic
      progenitors rather than to lineage-committed cells.
  - reference: PMID:35247902
    reference_title: ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of ZNF384 FO early in hematopoiesis results in binding and
      deregulation of key hematopoietic regulators, skewing of hematopoiesis,
      and priming for leukemic transformation. These results reveal the
      interplay between cell of origin and expression of ZNF384 FO to mediate
      lineage ambiguity and leukemia development.
    explanation: >-
      Functional mouse and human HSPC modelling shows the cell of origin is a
      required co-determinant of lineage ambiguity, supporting the causal role
      this node assigns to the progenitor compartment.
  downstream:
  - target: Failure of Lineage Commitment
    causal_link_type: DIRECT
    description: >-
      Transformation of a cell upstream of lineage commitment leaves the
      normal lineage-specification machinery operating in an uncommitted
      state.
  - target: BCR-ABL1 Kinase-Driven Proliferative Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - acquisition of t(9;22) in the multipotent progenitor compartment
    description: >-
      When BCR::ABL1 is acquired in a multipotent rather than a
      lineage-committed progenitor, the resulting leukemia is ambiguous
      rather than purely lymphoid or myeloid.
  - target: KMT2A Rearrangement and Aberrant HOXA Transcriptional Program
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - acquisition of an 11q23.3 KMT2A fusion in an immature progenitor
    description: >-
      KMT2A fusions arising in an immature progenitor produce leukemias with
      stem-like and mixed-lineage programs.
- name: Failure of Lineage Commitment
  biological_scale: CELLULAR
  description: >-
    Normal hematopoietic lineage choice is enforced by mutually antagonistic
    transcription factor networks (PU.1/SPI1 and CEBPA for myeloid, EBF1 and
    PAX5 for B, NOTCH1 and BCL11B for T). In MPAL these networks are
    disrupted or incompletely resolved, so no single program is consolidated
    and lineage-restricting feedback loops fail to close. The blast is left in
    a promiscuous, multi-lineage-primed transcriptional state.
  genes:
  - preferred_term: SPI1
    term:
      id: hgnc:11241
      label: SPI1
  - preferred_term: PAX5
    term:
      id: hgnc:8619
      label: PAX5
  - preferred_term: EBF1
    term:
      id: hgnc:3126
      label: EBF1
  - preferred_term: BCL11B
    term:
      id: hgnc:13222
      label: BCL11B
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  - preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: regulation of myeloid cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0045637
      label: regulation of myeloid cell differentiation
  - preferred_term: B cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030183
      label: B cell differentiation
  - preferred_term: T cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030217
      label: T cell differentiation
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that the cell of origin and founding lesions,
      rather than an accumulation of distinct genomic alterations, prime tumour
      cells for lineage promiscuity.
    explanation: >-
      States explicitly that lineage promiscuity in MPAL is a property of the
      cell of origin and founding lesion rather than of accumulated mutations,
      which is the failure-of-commitment model captured by this node.
  - reference: PMID:31792411
    reference_title: Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite widespread epigenetic heterogeneity within the patient cohort, we
      observe common malignant signatures across patients as well as
      patient-specific regulatory features that are shared across phenotypic
      compartments of individual patients.
    explanation: >-
      Single-cell chromatin and transcriptome profiling of MPAL patients shows
      regulatory features shared across the different phenotypic (lineage)
      compartments of the same leukemia, consistent with one unresolved
      multi-lineage program rather than two independent lineage programs.
  - reference: PMID:39813682
    reference_title: Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transcriptionally, AML-MP shows enrichment for stemness signatures and a
      relative deficit of transcription factors critical for myeloid and
      lymphoid differentiation.
    explanation: >-
      Supports a transcription-factor-deficit model of failed lineage
      resolution in mixed-phenotype acute leukemia; marked PARTIAL because the
      quoted finding is reported for the AML-with-mixed-phenotype group rather
      than for MPAL proper.
  downstream:
  - target: Cross-Lineage Antigen Co-expression
    causal_link_type: DIRECT
    description: >-
      An unresolved multi-lineage transcriptional program is transcribed and
      translated into simultaneous expression of myeloid and lymphoid
      lineage-defining proteins.
  - target: Lineage Plasticity and Therapy Escape
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - retention of alternative lineage transcriptional programs in an
      accessible chromatin state
    description: >-
      Because alternative lineage programs remain accessible rather than
      silenced, the clone can shift lineage under selective pressure.
  - target: Stem-like Transcriptional State and Epigenetic Lineage Programming
    causal_link_type: DIRECT
    description: >-
      Failure to consolidate a lineage program leaves the blast in the
      stem-like, high-differentiation-potential transcriptional state that
      single-cell profiling identifies as the shared feature of MPAL.
- name: Stem-like Transcriptional State and Epigenetic Lineage Programming
  biological_scale: MOLECULAR
  description: >-
    Multiomic single-cell profiling shows that MPAL blasts, irrespective of
    their surface immunophenotype or driver genotype, converge on a shared
    stem-cell-like transcriptional program indicating high differentiation
    potential; the degree of that stemness tracks with survival. Genome-wide
    methylation separates MPAL into AML-like and ALL-like epigenetic classes
    whose lineage-commitment gene expression differs, so the epigenetic state,
    not only the mutation set, determines which lineage programs the blast can
    access. This node is the mechanistic bridge between a failed commitment
    decision and both the observed cross-lineage phenotype and the capacity
    for lineage switch.
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: stem cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0048863
      label: stem cell differentiation
  - preferred_term: hemopoiesis
    modifier: ABNORMAL
    term:
      id: GO:0030097
      label: hemopoiesis
  evidence:
  - reference: PMID:39294124
    reference_title: Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that neither genetic profile nor transcriptome reliably correlate
      with specific MPAL immunophenotypes. Despite this, we find that MPAL
      blasts express a shared stem cell-like transcriptional profile indicative
      of high differentiation potential. Patients with the highest
      differentiation potential demonstrate inferior survival in our dataset.
    explanation: >-
      Multiomic single-cell profiling of 14 newly diagnosed adult MPAL cases
      establishes the shared stem-like transcriptional state and links greater
      differentiation potential to worse survival.
  - reference: PMID:29991687
    reference_title: Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloid-B and myeloid-T MPAL show distinct mutation and methylation
      signatures that are associated with differences in lineage-commitment
      gene expressions.
    explanation: >-
      Integrative genomic and methylation analysis ties the epigenetic state of
      MPAL directly to lineage-commitment gene expression.
  - reference: PMID:29991687
    reference_title: Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL
      sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated
      with better clinical response when lineage-matched therapy is given.
    explanation: >-
      Shows the epigenetic lineage class is clinically actionable, supporting
      it as a real mechanistic layer rather than a descriptive one.
  - reference: PMID:37845689
    reference_title: Single-cell RNA sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      B/My and T/My MPAL blasts displayed distinct blast signatures.
      Transcriptomic analysis revealed that B/My MPAL profile overlaps with
      B-ALL and AML samples. Similarly, T/My MPAL exhibited overlap with T-ALL
      and AML samples.
    explanation: >-
      Pediatric single-cell transcriptomics shows each MPAL subtype's program
      overlaps both of its constituent lineages, the transcriptional
      counterpart of the mixed immunophenotype.
  downstream:
  - target: Cross-Lineage Antigen Co-expression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - simultaneous accessibility of myeloid and lymphoid enhancer landscapes
    description: >-
      An epigenetic state that keeps both myeloid and lymphoid programs
      accessible is transcribed into simultaneous cross-lineage antigen
      expression.
  - target: Lineage Plasticity and Therapy Escape
    causal_link_type: DIRECT
    description: >-
      High differentiation potential is precisely the property that permits a
      clone to relocate to another lineage under therapeutic pressure.
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - stem-like self-renewal capacity
    description: >-
      Stem-like self-renewal sustains the expanding leukemic population and is
      associated with inferior survival.
- name: BCR-ABL1 Kinase-Driven Proliferative Signaling
  biological_scale: MOLECULAR
  description: >-
    In BCR::ABL1-positive MPAL, the t(9;22) fusion produces a constitutively
    active ABL1 tyrosine kinase that drives RAS-MAPK and PI3K-AKT signaling
    independently of physiological growth factors. This supplies the
    proliferative and survival drive of the clone but does not by itself
    determine lineage, which is why the same fusion produces CML, Ph-positive
    B-ALL, or MPAL depending on the compartment in which it is acquired.
  subtypes:
  - MPAL BCR-ABL1
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  genes:
  - preferred_term: ABL1
    term:
      id: hgnc:76
      label: ABL1
  - preferred_term: BCR
    term:
      id: hgnc:1014
      label: BCR
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  - preferred_term: PI3K-AKT signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      Establishes t(9;22)/BCR::ABL1 as the most frequent recurrent lesion in
      WHO-defined MPAL, the lesion modelled by this node.
  - reference: PMID:25605373
    reference_title: How I treat mixed-phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      addition of a tyrosine kinase inhibitor in patients with t(9;22)
      translocation is recommended
    explanation: >-
      The therapeutic recommendation to add a kinase inhibitor for t(9;22)
      MPAL reflects the actionable kinase dependency asserted by this node.
  downstream:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - growth-factor-independent proliferation
    - apoptosis resistance
    description: >-
      Constitutive kinase output drives growth-factor-independent expansion of
      the ambiguous-lineage clone.
- name: KMT2A Rearrangement and Aberrant HOXA Transcriptional Program
  biological_scale: MOLECULAR
  description: >-
    Rearrangement of KMT2A at 11q23.3 replaces the wild-type methyltransferase
    with a fusion that recruits the DOT1L/super-elongation machinery to KMT2A
    target loci and enforces sustained expression of HOXA cluster genes and
    MEIS1. This locks the cell in a self-renewing, stem-like state in which
    lineage commitment cannot proceed, and it also underlies the well-described
    tendency of KMT2A-rearranged leukemias to switch lineage.
  subtypes:
  - MPAL KMT2A
  genes:
  - preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  - preferred_term: MEN1
    term:
      id: hgnc:7010
      label: MEN1
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: stem cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0048863
      label: stem cell differentiation
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      Documents 11q23/KMT2A rearrangement as a recurrent defining lesion in a
      WHO-defined MPAL cohort.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia with BCR::ABL1 fusion
      Mixed-phenotype acute leukaemia with KMT2A rearrangement
    explanation: >-
      WHO-HAEM5 elevates KMT2A rearrangement to a defining genetic abnormality
      of ambiguous-lineage acute leukemia.
  downstream:
  - target: Failure of Lineage Commitment
    causal_link_type: DIRECT
    description: >-
      The KMT2A fusion transcriptional program actively sustains an
      uncommitted, stem-like state instead of permitting lineage resolution.
  - target: Lineage Plasticity and Therapy Escape
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - maintenance of an immature multi-lineage-competent chromatin state
    description: >-
      KMT2A-rearranged clones are the archetype of therapy-associated lineage
      switch between lymphoid and myeloid phenotypes.
- name: ZNF384 Rearrangement and B/Myeloid Programming
  biological_scale: MOLECULAR
  description: >-
    Rearrangements that fuse the ZNF384 transcription factor to partners such
    as TCF3, EP300, CREBBP or TAF15 generate a chimeric transcriptional
    regulator that imposes a hybrid B-lymphoid/myeloid expression program.
    ZNF384 fusions are the recurrent alteration most characteristic of
    B/myeloid MPAL and link that subtype to the ZNF384-rearranged subgroup of
    B-ALL.
  subtypes:
  - MPAL B/myeloid NOS
  genes:
  - preferred_term: ZNF384
    term:
      id: hgnc:11955
      label: ZNF384
  cell_types:
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  biological_processes:
  - preferred_term: myeloid leukocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0002573
      label: myeloid leukocyte differentiation
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Identifies ZNF384 rearrangement as the recurrent lesion of B/myeloid
      MPAL.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukaemia with ZNF384 rearrangement
    explanation: >-
      WHO-HAEM5 recognizes ZNF384-rearranged MPAL as a named subtype under
      ambiguous-lineage leukemia with other defined genetic alterations.
  - reference: PMID:35247902
    reference_title: ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using viral expression in mouse and human hematopoietic stem and
      progenitor cells (HSPC) and a Ep300::Znf384 knockin mouse model, we show
      that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing,
      and self-renewal.
    explanation: >-
      Provides direct functional evidence that ZNF384 fusion oncoproteins
      cause myeloid skewing and self-renewal in hematopoietic progenitors.
  - reference: PMID:35247902
    reference_title: ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, ZNF384 FO occupy a subset of predominantly
      intragenic/enhancer regions with increased histone 3 lysine acetylation
      and deregulate expression of hematopoietic stem cell transcription
      factors.
    explanation: >-
      Defines the chromatin-level mechanism by which the chimeric ZNF384
      regulator reprograms hematopoietic transcription factor output.
  - reference: PMID:35247902
    reference_title: ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for
      fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO
      drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged
      xenograft to FLT3 inhibition in vivo.
    explanation: >-
      Shows the ZNF384 fusion produces B/myeloid leukemia in human progenitors
      and identifies FLT3 as a candidate dependency of this subtype.
  downstream:
  - target: Cross-Lineage Antigen Co-expression
    causal_link_type: DIRECT
    description: >-
      The chimeric ZNF384 regulator directly drives simultaneous B-lymphoid
      and myeloid antigen expression in the blast.
- name: Immature T-Lineage Program with Retained Myeloid Potential
  biological_scale: CELLULAR
  description: >-
    T/myeloid MPAL arises from a thymic-seeding or pre-thymic progenitor that
    has begun T-lineage specification (cytoplasmic CD3 is expressed) but has
    not extinguished myeloid potential. The genomic landscape overlaps
    extensively with early T-cell precursor ALL, with recurrent WT1, PHF6,
    RUNX1, ETV6 and NOTCH1 alterations and BCL11B enhancer hijacking, placing
    T/myeloid MPAL and ETP-ALL on a biological continuum.
  subtypes:
  - MPAL T/myeloid NOS
  genes:
  - preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  - preferred_term: PHF6
    term:
      id: hgnc:18145
      label: PHF6
  - preferred_term: ETV6
    term:
      id: hgnc:3495
      label: ETV6
  - preferred_term: BCL11B
    term:
      id: hgnc:13222
      label: BCL11B
  cell_types:
  - preferred_term: pro-T cell
    term:
      id: CL:0000827
      label: pro-T cell
  biological_processes:
  - preferred_term: T cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030217
      label: T cell differentiation
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Establishes both the recurrent biallelic WT1 lesion and the genomic
      continuity between T/myeloid MPAL and early T-cell precursor ALL that
      this node asserts.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      BCL11B rearrangements in MPAL T/
      Myeloid, ETP-ALL, acute leukaemia of ambiguous lineage (ALAL)
      and a subset of AML with minimal differentiation suggests a
      biologic continuum across these entities
    explanation: >-
      WHO-HAEM5 states that BCL11B rearrangement links T/myeloid MPAL, ETP-ALL
      and immature AML in a biologic continuum, supporting both the BCL11B
      lesion and the ETP-ALL overlap described here.
  - reference: PMID:37845689
    reference_title: Single-cell RNA sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed
      that T/My MPAL had greater overlap with ETP-ALL cases.
    explanation: >-
      Single-cell transcriptomics places T/myeloid MPAL closest to ETP-ALL,
      corroborating the immature-T-with-retained-myeloid-potential model.
  downstream:
  - target: Cross-Lineage Antigen Co-expression
    causal_link_type: DIRECT
    description: >-
      Partial T-lineage specification with retained myeloid competence yields
      blasts that satisfy both T and myeloid lineage-assignment criteria.
- name: Cross-Lineage Antigen Co-expression
  biological_scale: CELLULAR
  description: >-
    The defining, diagnostically operationalized event: blasts express
    lineage-assigning antigens of more than one lineage, either within a single
    population (biphenotypic) or as two coexisting populations (bilineal).
    WHO/ICC criteria assign myeloid lineage on myeloperoxidase expression or
    monocytic differentiation, T lineage on cytoplasmic or surface CD3, and B
    lineage on strong CD19 with at least one of CD79a, cytoplasmic CD22 or
    CD10, or weak CD19 with at least two of these. In acute undifferentiated
    leukemia the same machinery fails in the opposite direction and no lineage
    marker is expressed at all.
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  - preferred_term: precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  genes:
  - preferred_term: MPO
    term:
      id: hgnc:7218
      label: MPO
  - preferred_term: CD19
    term:
      id: hgnc:1633
      label: CD19
  biological_processes:
  - preferred_term: hemopoiesis
    modifier: ABNORMAL
    term:
      id: GO:0030097
      label: hemopoiesis
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T
      (4%), or trilineage (2%) combinations.
    explanation: >-
      Documents the actual distribution of cross-lineage antigen combinations
      that define MPAL in a WHO-criteria cohort.
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloid and T-lineage features were demonstrated by cytoplasmic
      myeloperoxidase and CD3; B-lineage features were demonstrated by at least
      2 B-lymphoid markers.
    explanation: >-
      Describes the marker-based lineage-assignment operationalization used to
      diagnose MPAL.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Myeloperoxidase Intensity in part exceeds 50% of mature neutrophil level
    explanation: >-
      The WHO-HAEM5 lineage-assignment table gives the quantitative
      myeloperoxidase threshold used to assign myeloid lineage.
  downstream:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - maturation arrest of the ambiguous-lineage blast
    description: >-
      Blasts arrested in an ambiguous, non-maturing state accumulate rather
      than terminally differentiating and dying.
  - target: Leukemia
    causal_link_type: DIRECT
    description: >-
      Demonstration of cross-lineage antigen co-expression on acute leukemia
      blasts is what establishes the diagnosis of mixed phenotype acute
      leukemia.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of
        hematopoietic malignancies in which blasts show markers of multiple
        developmental lineages and cannot be clearly classified as acute myeloid
        or lymphoblastic leukemias.
      explanation: >-
        The definition makes multi-lineage marker expression on the blasts
        constitutive of the leukemia diagnosis, which is exactly this edge.
- name: Clonal Blast Expansion and Bone Marrow Replacement
  biological_scale: TISSUE
  description: >-
    The transformed, maturation-arrested clone expands in the bone marrow,
    progressively displacing normal hematopoietic elements. Expansion is
    driven by growth-factor-independent proliferation and impaired apoptosis,
    and blasts spill into peripheral blood.
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of
      hematopoietic malignancies in which blasts show markers of multiple
      developmental lineages and cannot be clearly classified as acute myeloid
      or lymphoblastic leukemias.
    explanation: >-
      Establishes MPAL as an acute leukemia driven by an expanding blast
      population; marked PARTIAL because the quotation characterizes the
      lineage ambiguity rather than quantifying marrow replacement itself.
  downstream:
  - target: Bone Marrow Failure and Peripheral Cytopenias
    causal_link_type: DIRECT
    description: >-
      Physical and functional displacement of normal hematopoiesis by the
      expanding blast population.
  - target: Extramedullary Leukemic Infiltration
    causal_link_type: DIRECT
    description: >-
      Circulating blasts seed liver, spleen, lymph nodes and the central
      nervous system.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Extramedullary involvement (particularly CNS) is report- ed to be more
        frequent in comparison to ALL or AML. This difference can be partly
        explained by a relatively higher occurrence of hyperleukocytosis at the
        diagnosis
      explanation: >-
        The review attributes the excess extramedullary involvement in MPAL to
        the higher circulating blast burden, which is the mechanism this edge
        asserts.
  - target: Increased total leukocyte count
    causal_link_type: DIRECT
    description: >-
      Egress of blasts from marrow into blood raises the total leukocyte
      count.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        higher occurrence of hyperleukocytosis at the diagnosis
      explanation: >-
        Documents hyperleukocytosis as a characteristic finding at MPAL
        diagnosis, the peripheral-blood consequence of blast expansion.
  - target: Leukemia
    causal_link_type: DIRECT
    description: >-
      Blast expansion in marrow and blood constitutes the acute leukemia
      itself.
- name: Bone Marrow Failure and Peripheral Cytopenias
  biological_scale: ORGANISM
  description: >-
    Replacement of normal marrow by blasts suppresses erythropoiesis,
    granulopoiesis and megakaryopoiesis, producing the cytopenia triad of
    anemia, neutropenia and thrombocytopenia that generates most of the
    presenting clinical features of MPAL.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: hemopoiesis
    modifier: DECREASED
    term:
      id: GO:0030097
      label: hemopoiesis
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      States that MPAL presents with the anemia, hemorrhage and infection
      triad, that is, the clinical consequences of marrow-failure cytopenias.
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: Suppressed erythropoiesis lowers hemoglobin.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        infiltration of bone mar- row with suppression of hematopoiesis
      explanation: >-
        Names marrow infiltration with suppression of hematopoiesis as the
        mechanism producing the presenting cytopenias, of which anemia is one.
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: Suppressed megakaryopoiesis lowers the platelet count.
  - target: Decreased total neutrophil count
    causal_link_type: DIRECT
    description: Suppressed granulopoiesis lowers the neutrophil count.
  - target: Fatigue
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - anemia and reduced oxygen-carrying capacity
    description: Anemia produces fatigue and exercise intolerance.
  - target: Pallor
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - anemia
    description: Reduced hemoglobin produces mucocutaneous pallor.
  - target: Abnormal bleeding
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - thrombocytopenia
    description: Thrombocytopenia impairs primary hemostasis.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        The signs of MPAL patients are similar to those seen
        in patients with other types of AL, including anemic syn- drome,
        hemorrhage and infection
      explanation: >-
        Hemorrhage is named among the presenting signs attributed to
        marrow-failure biology; PARTIAL because the quotation does not itself
        establish the thrombocytopenia intermediate.
  - target: Petechiae
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - thrombocytopenia
    description: Thrombocytopenia produces petechial skin and mucosal bleeding.
  - target: Recurrent infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neutropenia and impaired innate immune defence
    description: Neutropenia predisposes to bacterial and fungal infection.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        The signs of MPAL patients are similar to those seen
        in patients with other types of AL, including anemic syn- drome,
        hemorrhage and infection
      explanation: >-
        Infection is named among the presenting signs attributed to
        marrow-failure biology; PARTIAL because the quotation does not itself
        establish the neutropenia intermediate.
  - target: Fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neutropenic infection
    - leukemic cytokine release
    description: >-
      Fever arises from neutropenic infection and from cytokine release by the
      leukemic clone.
- name: Extramedullary Leukemic Infiltration
  biological_scale: ORGANISM
  description: >-
    Circulating ambiguous-lineage blasts infiltrate reticuloendothelial and
    sanctuary tissues, producing organomegaly, lymphadenopathy, periosteal bone
    pain and, in a minority, central nervous system disease that motivates
    routine CNS-directed prophylaxis.
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The involvement of the CNS at presentation was noted in 5
      (18.5%) cases among 27 children with MPAL diagnosed
      according to the EGIL criteria and in 2 (18.2%) out of 11
      children meeting the 2008 WHO criteria
    explanation: >-
      Quantifies central nervous system involvement at presentation in
      pediatric MPAL, an extramedullary infiltration site.
  downstream:
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
    description: Blast infiltration of liver and spleen produces organomegaly.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        hepatospleno- megaly and lymphadenomegaly were more common in MPAL than
        in AML
      explanation: >-
        Hepatosplenomegaly is reported as more common in MPAL than in AML,
        the organ-infiltration consequence this edge asserts.
  - target: Lymphadenopathy
    causal_link_type: DIRECT
    description: Nodal blast infiltration produces lymphadenopathy.
    evidence:
    - reference: PMID:28422191
      reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        hepatospleno- megaly and lymphadenomegaly were more common in MPAL than
        in AML
      explanation: >-
        Lymphadenomegaly is reported as more common in MPAL than in AML, the
        nodal-infiltration consequence this edge asserts.
  - target: Bone pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - marrow cavity expansion and periosteal stretch
    description: Marrow packing and periosteal involvement cause bone pain.
- name: Lineage Plasticity and Therapy Escape
  biological_scale: CELLULAR
  description: >-
    Because alternative lineage programs remain transcriptionally accessible,
    MPAL clones can shift immunophenotype under therapeutic pressure. This is
    seen as spontaneous lymphoid-to-myeloid switching at relapse, and as
    antigen-loss or lineage-switch escape from lineage-directed immunotherapy
    such as CD19-targeted CAR T cells and blinatumomab. Plasticity is a major
    reason MPAL responds poorly to single-lineage-directed strategies and a
    principal driver of its inferior outcome relative to ALL.
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: hematopoietic progenitor cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0002244
      label: hematopoietic progenitor cell differentiation
  evidence:
  - reference: PMID:39813682
    reference_title: Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, AML-MP rarely switches to a lymphoid
      immunophenotype after treatment, in contrast to MPAL ... 10/28 35.7%;
      P = .0003
    explanation: >-
      Quantifies post-treatment immunophenotypic (lineage) switching in MPAL at
      roughly one third of cases (10/28, 35.7%) against 2.5% in AML with a
      mixed phenotype, directly supporting therapy-associated lineage
      plasticity. The quotation is elided at the AML-MP arm of the comparison;
      the square brackets the journal places around the percentage are dropped
      because the validator treats bracketed spans as editorial insertions.
  - reference: PMID:37474833
    reference_title: Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole genome sequencing unambiguously revealed the AML derived from the
      initial ALL, with distinct driver mutations that were detectable before
      emergence. Extensive prior diversification and subsequent clonal
      selection underpins this fatal lineage switch.
    explanation: >-
      Whole-genome phylogeny shows a lymphoid-to-myeloid lineage switch under
      anti-CD19 pressure arises by selection of a pre-existing subclone, the
      escape mechanism this node describes.
  - reference: PMID:41063702
    reference_title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The use of lineage-specific targeted approaches may result in therapeutic
      pressure and lineage switch in patients with acute leukemia with
      multi-phenotypic potential.
    explanation: >-
      A 2025 review states the general principle that lineage-directed therapy
      selects for lineage switch in multi-phenotypic acute leukemia.
  downstream:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - selection of a phenotypically switched, therapy-resistant subclone
    description: >-
      A lineage-switched subclone escapes lineage-directed therapy and
      re-expands, producing refractory or relapsed disease.
phenotypes:
- category: Hematologic
  name: Leukemia
  description: >-
    Acute leukemia with blasts of ambiguous lineage in bone marrow and
    peripheral blood.
  phenotype_term:
    preferred_term: Mixed phenotype acute leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of
      hematopoietic malignancies in which blasts show markers of multiple
      developmental lineages and cannot be clearly classified as acute myeloid
      or lymphoblastic leukemias.
    explanation: >-
      Establishes MPAL as an acute leukemia, the defining phenotype of this
      entry.
- category: Hematologic
  name: Anemia
  description: >-
    Normocytic anemia from marrow replacement, frequently symptomatic at
    presentation.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states MPAL presents with the anemia, hemorrhage and infection
      triad of marrow failure; marked PARTIAL because the quotation groups the
      cytopenia consequences rather than reporting this individual
      cytopenia separately.
- category: Hematologic
  name: Thrombocytopenia
  description: Reduced platelet count from suppressed megakaryopoiesis.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states MPAL presents with the anemia, hemorrhage and infection
      triad of marrow failure; marked PARTIAL because the quotation groups the
      cytopenia consequences rather than reporting this individual
      cytopenia separately.
- category: Hematologic
  name: Decreased total neutrophil count
  description: Neutropenia from suppressed granulopoiesis.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states MPAL presents with the anemia, hemorrhage and infection
      triad of marrow failure; marked PARTIAL because the quotation groups the
      cytopenia consequences rather than reporting this individual
      cytopenia separately.
- category: Hematologic
  name: Increased total leukocyte count
  description: >-
    Leukocytosis due to circulating blasts; MPAL frequently presents with
    higher white cell counts than lineage-committed acute leukemias.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Extramedullary involvement (particularly CNS) is report- ed to be more
      frequent in comparison to ALL or AML. This difference can be partly
      explained by a relatively higher occurrence of hyperleukocytosis at the
      diagnosis
    explanation: >-
      The review states directly that hyperleukocytosis occurs relatively more
      often at diagnosis in MPAL, and uses it to explain the excess
      extramedullary involvement. No frequency band is asserted.
  - reference: PMID:41477275
    reference_title: Mixed phenotype acute leukemia, the dissection of an enigmatic disease in the era of novel therapies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adverse prognostic factors include KMT2Ar, elevated leukocyte counts,
      extramedullary disease, and bilineage disease biology.
    explanation: >-
      A 2025 MPAL review names elevated leukocyte counts among the recognised
      adverse prognostic factors, confirming leukocytosis is both a feature and
      a risk marker of the disease.
- category: Constitutional
  name: Fatigue
  description: Fatigue and exercise intolerance secondary to anemia.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states that MPAL patients present with an anemic syndrome;
      fatigue is the symptomatic expression of that anemia. Marked PARTIAL
      because fatigue is not named separately and no frequency is asserted.
- category: Constitutional
  name: Pallor
  description: Mucocutaneous pallor secondary to anemia.
  phenotype_term:
    preferred_term: Pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states that MPAL patients present with an anemic syndrome, of
      which mucocutaneous pallor is the cardinal sign. Marked PARTIAL because
      pallor is not named separately and no frequency is asserted.
- category: Constitutional
  name: Fever
  description: >-
    Fever at presentation, from neutropenic infection or from the leukemic
    process itself.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review names infection among the presenting signs of MPAL, the usual
      proximate cause of fever at diagnosis. Marked PARTIAL because fever itself
      is not named and no frequency is asserted.
- category: Hematologic
  name: Abnormal bleeding
  description: Bleeding diathesis secondary to thrombocytopenia.
  phenotype_term:
    preferred_term: Bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review names hemorrhage directly among the presenting signs of MPAL.
      No frequency band is asserted.
- category: Dermatologic
  name: Petechiae
  description: Petechial skin and mucosal hemorrhage from thrombocytopenia.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review names hemorrhage among the presenting signs of MPAL; petechiae
      are its characteristic cutaneous form in thrombocytopenic marrow failure.
      Marked PARTIAL because petechiae are not named separately.
- category: Immunologic
  name: Recurrent infections
  description: Infections related to neutropenia and to functional immune failure.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review names infection directly among the presenting signs of MPAL.
      Marked PARTIAL because the quotation does not establish that the
      infections are recurrent, and no frequency is asserted.
- category: Gastrointestinal
  name: Hepatosplenomegaly
  description: Hepatic and splenic enlargement from leukemic infiltration.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      hepatospleno- megaly and lymphadenomegaly were more common in MPAL than
      in AML
    explanation: >-
      The review states directly that hepatosplenomegaly is more common in MPAL
      than in AML. The quotation reproduces the cached line-break hyphenation of
      "hepatospleno-megaly".
- category: Hematologic
  name: Lymphadenopathy
  description: Nodal enlargement from leukemic infiltration.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      hepatospleno- megaly and lymphadenomegaly were more common in MPAL than
      in AML
    explanation: >-
      The review states directly that lymphadenomegaly is more common in MPAL
      than in AML.
- category: Musculoskeletal
  name: Bone pain
  description: Bone and joint pain from marrow expansion and periosteal involvement.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The signs of MPAL patients are similar to those seen
      in patients with other types of AL, including anemic syn- drome,
      hemorrhage and infection
    explanation: >-
      The review states that MPAL presents with the same marrow-failure signs as
      other acute leukemias, of which bone pain from marrow expansion is one.
      Marked PARTIAL because bone pain is not named in the quotation and no
      frequency is asserted.
genetic:
- name: BCR::ABL1
  notes: >-
    t(9;22)(q34.1;q11.2) generating the BCR::ABL1 fusion tyrosine kinase.
    Defines the WHO/ICC genetic subtype of MPAL and creates the actionable
    dependency treated with tyrosine kinase inhibitors.
  subtype: MPAL BCR-ABL1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ABL1
    term:
      id: hgnc:76
      label: ABL1
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      Quantifies t(9;22)/Philadelphia-chromosome frequency at 20% of the
      100-patient WHO-2008 reference series.
  - reference: PMID:32419244
    reference_title: "Prognostic impact of Philadelphia chromosome in mixed phenotype acute leukemia (MPAL): A cancer registry analysis on real-world outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On multivariate analyses and after adjustment for age, year of diagnosis
      and chemotherapy status, Ph+ MPAL patients had reduced risk of death in
      comparison to Ph(-) MPAL patients
    explanation: >-
      SEER registry analysis establishes BCR::ABL1/Philadelphia-chromosome
      status as a prognostically decisive somatic driver in MPAL.
- name: KMT2A rearrangement
  notes: >-
    Rearrangement of KMT2A at 11q23.3 with a variety of fusion partners.
    Defines the second WHO/ICC genetic subtype of MPAL and is enriched in
    infants.
  subtype: MPAL KMT2A
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      Quantifies 11q23/KMT2A rearrangement frequency at 8% of the WHO-2008
      reference series.
  - reference: PMID:32419244
    reference_title: "Prognostic impact of Philadelphia chromosome in mixed phenotype acute leukemia (MPAL): A cancer registry analysis on real-world outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So, MLL+ MPAL had the worst outcome with a 10-fold increased risk of
      death in comparison to Ph+ MPAL patients (HR = 10.2, P < .001).
    explanation: >-
      Establishes KMT2A/MLL rearrangement as the most adverse prognostic
      somatic driver in MPAL.
- name: ZNF384 rearrangement
  notes: >-
    Fusions of ZNF384 to partners including TCF3, EP300, CREBBP and TAF15;
    the recurrent alteration most characteristic of B/myeloid MPAL.
  subtype: MPAL B/myeloid NOS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ZNF384
    term:
      id: hgnc:11955
      label: ZNF384
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Landmark genomics establishes ZNF384 rearrangement as the characteristic
      somatic driver of B/myeloid MPAL.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ﬁrst subtype is MPAL with ZNF384 rearrangement, which commonly has a
      B/myeloid immunophenotype and is identiﬁed in ~50% of pediatric
      B/myeloid MPAL with fusion partners including TCF3, EP300, TAF15, and
      CREBBP.
    explanation: >-
      WHO-HAEM5 recognizes ZNF384-rearranged MPAL as a named subtype, gives
      its B/myeloid immunophenotype, its ~50% share of pediatric B/myeloid
      MPAL, and its fusion partners.
- name: WT1
  notes: >-
    WT1 alterations are recurrent in T/myeloid MPAL and are shared with early
    T-cell precursor ALL.
  subtype: MPAL T/myeloid NOS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Landmark genomics establishes biallelic WT1 alteration as characteristic
      of T/myeloid MPAL.
- name: PHF6
  notes: >-
    PHF6 loss-of-function alterations recur in T/myeloid MPAL, part of the
    shared T-lineage immature-leukemia landscape.
  subtype: MPAL T/myeloid NOS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: PHF6
    term:
      id: hgnc:18145
      label: PHF6
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Other genomic ﬁndings such as PHF6 mutations and PICALM::
    explanation: >-
      WHO-HAEM5 lists PHF6 mutation among the genomic findings enriched in
      MPAL that are not yet subtype-defining. The quoted span stops at the
      PICALM::MLLT10 fusion name because the cached text breaks that symbol
      across a line.
- name: RUNX1
  notes: >-
    RUNX1 alterations recur across MPAL and are associated with immature,
    stem-like leukemia phenotypes.
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we show that the two principal subtypes of MPAL, T/myeloid (T/M)
      and B/myeloid (B/M), are genetically distinct.
    explanation: >-
      The landmark genomic survey that catalogued the recurrent
      transcription-factor lesions of MPAL, RUNX1 among them. Support is
      PARTIAL because the abstract names only ZNF384 and WT1 explicitly; the
      RUNX1 finding is in the paper body.
- name: NOTCH1
  notes: >-
    NOTCH1 activating alterations occur in T/myeloid MPAL, shared with the
    T-ALL spectrum.
  subtype: MPAL T/myeloid NOS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  evidence:
  - reference: PMID:30209392
    reference_title: The genetic basis and cell of origin of mixed phenotype acute leukaemia.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1
      alterations are common in T/M MPAL, which shares genomic features with
      early T-cell precursor acute lymphoblastic leukaemia.
    explanation: >-
      Establishes that T/myeloid MPAL shares its genomic landscape with early
      T-cell precursor ALL, the context for its NOTCH1 lesions. Support is
      PARTIAL because NOTCH1 is named in the paper body rather than the
      abstract.
- name: BCL11B
  notes: >-
    Structural rearrangements that hijack enhancers to BCL11B are recurrent in
    immature/ambiguous-lineage acute leukemias including T/myeloid MPAL.
  subtype: MPAL T/myeloid NOS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: BCL11B
    term:
      id: hgnc:13222
      label: BCL11B
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The other subtype is ALAL with BCL11B rearrangement, which has a more
      heterogenous immunophenotype ... in acute undifferentiated
      leukaemia (AUL) and ~20-30% of T/myeloid MPAL.
    explanation: >-
      WHO-HAEM5 establishes BCL11B rearrangement as a defined
      ambiguous-lineage subtype and quantifies its share of T/myeloid MPAL at
      20-30%.
diagnosis:
- name: Multiparameter flow cytometric immunophenotyping
  description: >-
    The definitive diagnostic modality. WHO/ICC lineage-assignment criteria are
    applied to blast populations: myeloid lineage on myeloperoxidase or
    monocytic differentiation markers, T lineage on cytoplasmic or surface CD3,
    B lineage on CD19-anchored marker combinations. MPAL is diagnosed when more
    than one lineage is assigned, either in one blast population or across two.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Myeloperoxidase Intensity in part exceeds 50% of mature neutrophil level
    explanation: >-
      The WHO-HAEM5 lineage-assignment table specifies the quantitative flow
      cytometric intensity thresholds on which the diagnosis rests.
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloid and T-lineage features were demonstrated by cytoplasmic
      myeloperoxidase and CD3; B-lineage features were demonstrated by at least
      2 B-lymphoid markers.
    explanation: >-
      Describes application of the marker-based lineage-assignment rules in
      practice.
- name: Cytogenetics and molecular testing
  description: >-
    Karyotype, FISH and molecular assays identify BCR::ABL1 and KMT2A
    rearrangements, which define the genetic subtypes and change therapy.
    Sequencing additionally detects ZNF384 fusions and the WT1/PHF6/RUNX1/
    NOTCH1 lesions characteristic of T/myeloid disease.
  evidence:
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements
      (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes.
    explanation: >-
      Demonstrates the diagnostic yield of karyotype and FISH in WHO-defined
      MPAL.
  - reference: PMID:29991687
    reference_title: Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with the mixed immunophenotype, both AML-type and ALL-type
      mutations are detected in MPAL.
    explanation: >-
      Supports broad sequencing rather than a lineage-restricted panel, since
      both myeloid- and lymphoid-typical mutations occur.
- name: Bone marrow aspirate and biopsy
  description: >-
    Establishes blast percentage, marrow cellularity and degree of normal
    hematopoietic displacement, and provides material for immunophenotyping
    and genomics.
- name: Cerebrospinal fluid examination
  description: >-
    Lumbar puncture with cytology and flow cytometry assesses central nervous
    system involvement and is combined with intrathecal prophylaxis.
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The involvement of the CNS at presentation was noted in 5
      (18.5%) cases among 27 children with MPAL diagnosed
      according to the EGIL criteria and in 2 (18.2%) out of 11
      children meeting the 2008 WHO criteria
    explanation: >-
      Documents a clinically meaningful frequency of CNS involvement at
      presentation, justifying routine CSF assessment.
- name: Measurable residual disease monitoring
  description: >-
    Flow cytometric (and where available molecular) measurable residual disease
    assessment at end of induction and end of consolidation. MRD must be
    designed at diagnosis to track every abnormal blast compartment, because
    MPAL clones can shift phenotype. End-of-induction MRD is the strongest
    early prognostic variable in pediatric MPAL and is the proposed basis for
    therapy adaptation, including the decision to proceed to transplant.
  evidence:
  - reference: PMID:32060402
    reference_title: "Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in
      most patients (70%). EOI MRD positivity was predictive of 5-year EFS
      (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003).
    explanation: >-
      Quantifies the prognostic weight of end-of-induction MRD in a
      centrally reviewed pediatric MPAL cohort.
differential_diagnoses:
- name: Acute myeloid leukemia with aberrant lymphoid antigen expression
  disease_term:
    preferred_term: acute myeloid leukemia with aberrant lymphoid antigen expression
    term:
      id: MONDO:0018874
      label: acute myeloid leukemia
  description: >-
    AML blasts frequently express individual lymphoid antigens such as CD7 or
    CD19 without meeting formal lineage-assignment thresholds; this is
    aberrant antigen expression, not MPAL.
  distinguishing_features:
  - MPAL requires formal WHO/ICC lineage-assignment criteria for two lineages
  - single aberrant antigens without cytoplasmic CD3 or CD19-anchored
    combinations do not assign a second lineage
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Myeloperoxidase Intensity in part exceeds 50% of mature neutrophil level
    explanation: >-
      WHO-HAEM5 sets a quantitative intensity threshold for lineage
      assignment, which is what separates true MPAL from AML carrying
      sub-threshold aberrant lymphoid antigens; PARTIAL because the quoted row
      gives the myeloid threshold rather than the full rule set.
- name: Early T-cell precursor acute lymphoblastic leukemia
  disease_term:
    preferred_term: early T-cell precursor acute lymphoblastic leukemia
    term:
      id: MONDO:0100291
      label: early T cell progenitor acute lymphoblastic leukemia
  description: >-
    ETP-ALL shares an immature immunophenotype, myeloid/stem antigen
    expression and much of its genomic landscape with T/myeloid MPAL.
  distinguishing_features:
  - ETP-ALL is myeloperoxidase-negative by definition
  - T/myeloid MPAL satisfies myeloid lineage assignment, usually via
    myeloperoxidase
  evidence:
  - reference: PMID:37845689
    reference_title: Single-cell RNA sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed
      that T/My MPAL had greater overlap with ETP-ALL cases.
    explanation: >-
      Quantifies the transcriptional proximity of T/myeloid MPAL to ETP-ALL,
      which is why ETP-ALL is the principal differential for this subtype.
- name: Acute undifferentiated leukemia
  disease_term:
    preferred_term: acute undifferentiated leukemia
    term:
      id: MONDO:0020321
      label: acute undifferentiated leukemia
  description: >-
    AUL blasts express no lineage-defining marker at all rather than more than
    one.
  distinguishing_features:
  - AUL assigns no lineage; MPAL assigns two or more
  evidence:
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute undifferentiated leukemia (AUL) is rare and defined by the absence
      of bona fide myeloid and lymphoid markers.
    explanation: >-
      Defines AUL by absence of lineage-defining markers, the exact inverse of
      the MPAL requirement that two or more lineages be assigned.
- name: Acute lymphoblastic leukemia
  disease_term:
    preferred_term: acute lymphoblastic leukemia
    term:
      id: MONDO:0004967
      label: acute lymphoblastic leukemia
  description: >-
    Lineage-committed B-ALL or T-ALL without qualifying cross-lineage myeloid
    antigen expression.
  distinguishing_features:
  - absence of myeloperoxidase or monocytic differentiation markers
- name: Blastic plasmacytoid dendritic cell neoplasm
  disease_term:
    preferred_term: blastic plasmacytoid dendritic cell neoplasm
    term:
      id: MONDO:0019467
      label: CD4+/CD56+ hematodermic neoplasm
  description: >-
    An immature CD4+/CD56+/CD123+ neoplasm that can mimic ambiguous-lineage
    leukemia.
  distinguishing_features:
  - characteristic CD123/TCL1/CD303 profile without myeloid or lymphoid
    lineage assignment
- name: Acute myeloid leukemia with a mixed phenotype
  disease_term:
    preferred_term: acute myeloid leukemia with a mixed phenotype (AML-MP)
    term:
      id: MONDO:0018874
      label: acute myeloid leukemia
  description: >-
    Acute myeloid leukemia that displays a mixed immunophenotype but is
    biologically and clinically distinct from de novo MPAL, with more frequent
    RUNX1 and TP53 mutations, inferior response, and little capacity for
    post-treatment lineage switch. Recognizing it matters because it responds
    poorly to the ALL-directed induction that benefits true MPAL.
  distinguishing_features:
  - enrichment for RUNX1 and TP53 driver mutations
  - inferior response to induction
  - rarely switches to a lymphoid immunophenotype after treatment
  evidence:
  - reference: PMID:39813682
    reference_title: Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and TP53 mutations as a driver
      are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment
      for stemness signatures and a relative deficit of transcription factors
      critical for myeloid and lymphoid differentiation.
    explanation: >-
      Genomic and transcriptomic separation of AML with mixed phenotype from
      MPAL, the basis for treating them as distinct diagnoses.
  - reference: PMID:39813682
    reference_title: Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AML-MP has inferior responses (hazard ratio, 12.5; 95% confidence
      interval, 2.72-57.8; P = .001), whereas MPAL has better responses to
      ALL-directed treatment.
    explanation: >-
      Establishes the clinical consequence of the distinction: ALL-directed
      therapy benefits MPAL but not AML with a mixed phenotype.
- name: Acute myeloid leukemia with defining recurrent genetic abnormalities
  disease_term:
    preferred_term: acute myeloid leukemia with defining recurrent genetic abnormalities
    term:
      id: MONDO:0018874
      label: acute myeloid leukemia
  description: >-
    A leukemia carrying an AML-defining lesion such as t(8;21)/RUNX1::RUNX1T1,
    inv(16)/CBFB::MYH11 or t(15;17)/PML::RARA is classified as that AML entity
    even if the blasts show a mixed immunophenotype, and is excluded from MPAL
    by WHO and ICC convention. Note that MONDO's umbrella term for this WHO
    grouping (MONDO:0020078, "acute myeloid leukemia with recurrent genetic
    anomaly") is obsolete and the individual lesion-specific children are too
    narrow to stand for the grouping, so the differential is anchored on the
    parent MONDO:0018874 with a more specific preferred_term.
  distinguishing_features:
  - presence of an AML-defining recurrent genetic abnormality overrides the
    mixed immunophenotype
treatments:
- name: ALL-Type Induction Chemotherapy
  description: >-
    Multi-agent lymphoid-type induction (vincristine, corticosteroid,
    anthracycline, asparaginase backbone) is the preferred initial regimen for
    most MPAL, with retrospective and registry data favouring ALL-directed over
    AML-directed induction for remission rates.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: vincristine
      term:
        id: CHEBI:28445
        label: vincristine
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
    - preferred_term: daunorubicin
      term:
        id: CHEBI:41977
        label: daunorubicin
    - preferred_term: asparaginase
      term:
        id: NCIT:C286
        label: Asparaginase
  target_mechanisms:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:29550836
    reference_title: "Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using either definition of MPAL, ALL-therapy is associated with higher
      initial remission rates for MPAL and is at least equivalent to more
      intensive AML therapy for long-term survival.
    explanation: >-
      Systematic review and meta-analysis of 1,499 patients supports ALL-type
      induction as the preferred initial regimen.
  - reference: PMID:21228332
    reference_title: "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5
      patients responded to the combination therapy.
    explanation: >-
      Direct comparison in a WHO-defined cohort shows markedly higher response
      to ALL-type than AML-type induction.
  - reference: PMID:31661160
    reference_title: "Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results of the COG MPAL cohort and a literature review suggest
      that ALL chemotherapy without HSCT may be the preferred initial therapy.
    explanation: >-
      The Children's Oncology Group task force concludes ALL-type chemotherapy
      is the preferred initial approach in pediatric MPAL.
  - reference: PMID:36959485
    reference_title: "Multicenter retrospective analysis of clinical outcome of adult patients with mixed-phenotype acute leukemia treated with acute myeloid leukemia-like or acute lymphoblastic leukemia-like chemotherapy and impact of allogeneic stem cell transplantation: a Campus ALL study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The complete remission (CR) rate was 67.6% and an ALL-like therapy was
      associated with a better CR rate (P = 0.048).
    explanation: >-
      A 77-patient adult multicenter series independently confirms the higher
      complete remission rate with ALL-like induction.
  - reference: PMID:33544265
    reference_title: "Mixed Phenotype Acute Leukemia: Current Approaches to Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The preponderance of retrospective data supports beginning therapy with
      ALL directed regimens.
    explanation: >-
      Review conclusion that the retrospective evidence base favours ALL-directed
      initial therapy, while flagging its retrospective nature.
- name: BCR::ABL1 Tyrosine Kinase Inhibitor Therapy
  description: >-
    Imatinib or a second/third-generation tyrosine kinase inhibitor added to
    chemotherapy for BCR::ABL1-positive MPAL, targeting the constitutively
    active fusion kinase.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: BCR-ABL1 Kinase-Driven Proliferative Signaling
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:25605373
    reference_title: How I treat mixed-phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      addition of a tyrosine kinase inhibitor in patients with t(9;22)
      translocation is recommended
    explanation: >-
      Expert treatment guidance recommends adding a TKI for t(9;22)-positive
      MPAL.
  - reference: PMID:41063702
    reference_title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      of tyrosine kinase inhibitors for Philadelphia chromosome- positive MPAL)
      over acute myeloid leukemia or hybrid approaches.
    explanation: >-
      A 2025 review reiterates ALL-directed therapy with a TKI for
      Philadelphia-positive MPAL over AML-type or hybrid approaches.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Consolidation with allogeneic transplant in first complete remission is
    widely used in MPAL given its inferior outcome relative to ALL, although
    the benefit is derived from retrospective series rather than randomized
    trials.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:28099272
    reference_title: "Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Allogeneic transplantation in first remission may be associated with
      improved survival compared with consolidation chemotherapy.
    explanation: >-
      Supports allogeneic transplant in first remission as a consolidation
      strategy in MPAL.
  - reference: PMID:25605373
    reference_title: How I treat mixed-phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The limited available data suggest that an "acute lymphoblastic
      leukemia-like" regimen followed by allogeneic stem-cell transplant may be
      advisable
    explanation: >-
      Expert guidance places allogeneic transplant after ALL-type induction in
      adult MPAL.
  - reference: PMID:32060402
    reference_title: "Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to adults with MPAL, ALL therapy without transplantation was
      adequate to treat most pediatric patients.
    explanation: >-
      Qualifies the transplant recommendation: in children who clear MRD,
      transplantation was not required, so this evidence partially refutes a
      universal transplant-in-CR1 policy while supporting it for adults.
  - reference: PMID:36959485
    reference_title: "Multicenter retrospective analysis of clinical outcome of adult patients with mixed-phenotype acute leukemia treated with acute myeloid leukemia-like or acute lymphoblastic leukemia-like chemotherapy and impact of allogeneic stem cell transplantation: a Campus ALL study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study shows that MPAL patients respond better to an ALL-like
      induction therapy; that consolidation therapy should include, whenever
      possible, an AlloSCT and that MRD negativity should be a primary endpoint
      of treatment.
    explanation: >-
      Adult multicenter data supporting allogeneic transplant as consolidation
      and measurable residual disease negativity as the treatment goal.
- name: Central Nervous System-Directed Prophylaxis
  description: >-
    Intrathecal chemotherapy is given as CNS prophylaxis following ALL-type
    protocols, because MPAL carries a meaningful risk of central nervous
    system involvement.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: intrathecal chemotherapy
    term:
      id: NCIT:C15750
      label: Intrathecal Chemotherapy
  target_mechanisms:
  - target: Extramedullary Leukemic Infiltration
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:28422191
    reference_title: "Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      intrathecal chemotherapy
      should be supplemented by prophylactic irradiation of the
      CNS
    explanation: >-
      The review describes intrathecal chemotherapy as the CNS-directed
      prophylaxis backbone in MPAL, intensified with cranial irradiation in
      high-white-count or Philadelphia-positive disease.
- name: Supportive Care
  description: >-
    Transfusion support, antimicrobial prophylaxis and management of tumor
    lysis syndrome address the consequences of marrow failure and of
    cytoreduction.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Bone Marrow Failure and Peripheral Cytopenias
    treatment_effect: MODULATES
- name: Blinatumomab (CD19-Directed T-Cell Engager)
  description: >-
    The CD19/CD3 bispecific T-cell engager blinatumomab is used in
    CD19-positive MPAL, principally in relapsed or refractory disease, in
    measurable-residual-disease-positive remission, and in KMT2A-rearranged
    infant protocols. Because it applies lineage-specific selective pressure,
    it carries a documented risk of antigen-loss or lineage-switch escape, so
    response should be monitored with lineage-aware measurable residual
    disease assessment.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: blinatumomab
      term:
        id: NCIT:C62528
        label: Blinatumomab
  target_mechanisms:
  - target: Cross-Lineage Antigen Co-expression
    treatment_effect: INHIBITS
    description: >-
      Targets the B-lineage antigen CD19 expressed by the cross-lineage blast
      population.
  evidence:
  - reference: PMID:41063702
    reference_title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The use of lineage-specific targeted approaches may result in therapeutic
      pressure and lineage switch in patients with acute leukemia with
      multi-phenotypic potential.
    explanation: >-
      Supports use of lineage-specific targeted agents in ambiguous-lineage
      leukemia while documenting their principal liability; marked PARTIAL
      because the quotation states the risk rather than establishing efficacy.
  - reference: PMID:37474833
    reference_title: Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19
      therapy occasionally develop acute myeloid leukemia (AML).
    explanation: >-
      Documents the failure mode of CD19-directed therapy in lineage-plastic
      leukemia, refuting any assumption of durable lineage-restricted control.
- name: CD19-Directed CAR T-Cell Therapy
  description: >-
    Autologous CD19-directed chimeric antigen receptor T cells are used
    off-label in CD19-positive relapsed or refractory MPAL, with the evidence
    base limited to case reports and small series extrapolated from B-ALL.
    Curated separately from blinatumomab because it is a distinct therapeutic
    modality (an engineered cell product rather than an antibody construct),
    even though the two share the CD19 target and the same lineage-switch
    escape liability.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: chimeric antigen receptor T-cell therapy
    term:
      id: NCIT:C126102
      label: Chimeric Antigen Receptor T-Cell Therapy
  target_mechanisms:
  - target: Cross-Lineage Antigen Co-expression
    treatment_effect: INHIBITS
    description: >-
      Redirected T cells lyse blasts bearing the B-lineage antigen CD19 within
      the cross-lineage blast population.
  evidence:
  - reference: PMID:37474833
    reference_title: Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19
      therapy occasionally develop acute myeloid leukemia (AML).
    explanation: >-
      Establishes that anti-CD19 cellular therapy is given in this setting
      while documenting its lineage-switch failure mode; PARTIAL because the
      report addresses escape rather than efficacy in MPAL.
  - reference: PMID:41063702
    reference_title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The use of lineage-specific targeted approaches may result in therapeutic
      pressure and lineage switch in patients with acute leukemia with
      multi-phenotypic potential.
    explanation: >-
      A 2025 review of ambiguous-lineage leukemia frames lineage-directed
      cellular and antibody therapy as usable but escape-prone; PARTIAL
      because it states the liability rather than establishing efficacy.
- name: BCL-2 Inhibition with Venetoclax
  description: >-
    Investigational in MPAL. Venetoclax combined with a hypomethylating agent
    is a lineage-agnostic, BCL-2-directed regimen now being tested
    prospectively in newly diagnosed MPAL, with treatment stratified by
    B/myeloid versus T/myeloid immunophenotype. No randomized efficacy data
    exist in MPAL and use outside trials is extrapolated from AML.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: venetoclax
      term:
        id: CHEBI:133021
        label: venetoclax
    - preferred_term: azacitidine
      term:
        id: CHEBI:2038
        label: 5-azacytidine
  target_mechanisms:
  - target: Clonal Blast Expansion and Bone Marrow Replacement
    treatment_effect: INHIBITS
    description: >-
      BCL-2 inhibition restores the apoptotic threshold of the
      maturation-arrested blast, a lineage-agnostic target that does not
      depend on which lineage the blast is expressing.
  evidence:
  - reference: clinicaltrials:NCT07573670
    reference_title: A Prospective, Open-Label, Single-Arm, Two-Cohort Phase 2 Clinical Study to Evaluate the Efficacy and Safety of Bcl-2 Inhibitor Combined With Azacitidine in the Treatment of Newly Diagnosed Mixed Phenotype Acute Leukemia
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eligible subjects are divided into two cohorts based on immunophenotype:
      Cohort A (T/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine, and
      Cohort B (B/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine +
      blinatumomab.
    explanation: >-
      A prospective MPAL-specific phase 2 study of BCL-2 inhibition plus
      azacitidine; PARTIAL because the trial is ongoing and no efficacy
      results are yet reported, and because the registration record names
      only "Bcl-2 Inhibitor" rather than a specific agent, so this record
      alone does not source the venetoclax identity of the CHEBI binding.
  - reference: PMID:41540127
    reference_title: "Efficacy and safety of mini-cvd combined with venetoclax and azacitidine in philadelphia chromosome-negative acute leukemia of ambiguous lineage: a single-center retrospective study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      who received induction therapy with the mini-CVD regimen
      (cyclophosphamide, vincristine, dexamethasone) combined with venetoclax
      and azacitidine ... Among this cohort, 92.3% of patients (12/13)
      achieved complete remission (CR).
    explanation: >-
      Names venetoclax and azacitidine explicitly as the BCL-2-directed
      combination actually given in acute leukemia of ambiguous lineage,
      which is what sources the CHEBI:133021 / CHEBI:2038 agent bindings that
      the trial record leaves as a generic drug class. PARTIAL rather than
      SUPPORT: this is a single-center retrospective series of 13
      Philadelphia-negative ALAL patients, venetoclax and azacitidine were
      given on a mini-CVD backbone rather than as the doublet the trial is
      testing, and the cohort is ALAL rather than MPAL-restricted, so it
      establishes the agent identity and clinical plausibility but not
      efficacy of the regimen in MPAL.
- name: FLT3 Inhibition in ZNF384-Rearranged Disease
  description: >-
    Investigational only. Preclinical work in ZNF384-rearranged leukemia
    identified FLT3 as a dependency, with in vivo response of a
    ZNF384-rearranged xenograft to FLT3 inhibition. No clinical efficacy has
    been established in MPAL.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gilteritinib
      term:
        id: NCIT:C116722
        label: Gilteritinib
  target_mechanisms:
  - target: ZNF384 Rearrangement and B/Myeloid Programming
    treatment_effect: INHIBITS
    description: >-
      Targets the FLT3 dependency created by the ZNF384 fusion transcriptional
      program.
  evidence:
  - reference: PMID:35247902
    reference_title: ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for
      fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO
      drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged
      xenograft to FLT3 inhibition in vivo.
    explanation: >-
      Xenograft evidence for FLT3 inhibitor sensitivity in ZNF384-rearranged
      leukemia; preclinical only, and it does not establish clinical benefit
      in MPAL.
clinical_trials:
- name: NCT05327894
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Interfant-21, an international collaborative treatment protocol adding
    blinatumomab for infants under one year with KMT2A-rearranged acute
    lymphoblastic leukemia or mixed phenotype acute leukemia.
  target_phenotypes:
  - preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: clinicaltrials:NCT05327894
    reference_title: Interfant-21 International Collaborative Treatment Protocol for Infants Under One Year With KMT2A-rearranged Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is a treatment protocol with blinatumomab for infants under 1
      year old who are diagnosed with acute lymphoblastic leukemia with a
      specific unfavorable genetic alteration.
    explanation: >-
      Interfant-21 enrolls infants with KMT2A-rearranged MPAL alongside
      KMT2A-rearranged ALL, reflecting the shared KMT2A biology curated here.
- name: NCT04872478
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Dose-escalation study of the oral MERTK/FLT3 inhibitor MRX-2843 in
    adolescents and adults with relapsed or refractory AML, ALL, or mixed
    phenotype acute leukemia.
  target_phenotypes:
  - preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: clinicaltrials:NCT04872478
    reference_title: An Open Label Evaluation Phase 1 Trial of the Safety and Pharmacokinetics of MRX-2843 in Adolescents and Adults With Relapsed/Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Mixed Phenotype Acute Leukemia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a Phase I, open-label, non-randomized, dose escalation study in
      adolescents and adults with relapsed/refractory acute myeloid leukemia,
      acute lymphoblastic leukemia, or mixed phenotype acute leukemia.
    explanation: >-
      An early-phase trial explicitly enrolling relapsed/refractory MPAL,
      illustrating the kinase-inhibitor strategy in ambiguous-lineage disease.
- name: NCT07573670
  phase: PHASE_II
  status: NOT_RECRUITING
  description: >-
    Two-cohort phase 2 study of a BCL-2 inhibitor plus azacitidine in newly
    diagnosed MPAL, with blinatumomab added for the B/myeloid cohort and
    allogeneic transplant planned for responders. One of the first
    prospective, immunophenotype-stratified, MPAL-specific treatment trials,
    directly addressing the open induction question curated here.
  target_phenotypes:
  - preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: clinicaltrials:NCT07573670
    reference_title: A Prospective, Open-Label, Single-Arm, Two-Cohort Phase 2 Clinical Study to Evaluate the Efficacy and Safety of Bcl-2 Inhibitor Combined With Azacitidine in the Treatment of Newly Diagnosed Mixed Phenotype Acute Leukemia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eligible subjects are divided into two cohorts based on immunophenotype:
      Cohort A (T/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine, and
      Cohort B (B/Myeloid MPAL) receives Bcl-2 Inhibitor + azacitidine +
      blinatumomab.
    explanation: >-
      A prospective MPAL-specific trial that stratifies treatment by B/myeloid
      versus T/myeloid immunophenotype, testing exactly the phenotype-directed
      approach this entry records as unresolved.
- name: NCT07222579
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Multicenter phase 2 study of subcutaneous blinatumomab in adults with
    CD19-positive MPAL across three cohorts: unfit newly diagnosed disease,
    MRD-positive remission, and morphologic relapsed/refractory disease. The
    most direct prospective test of CD19-directed immunotherapy in MPAL.
  target_phenotypes:
  - preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: clinicaltrials:NCT07222579
    reference_title: A Multicenter Phase II Study of Subcutaneous Blinatumomab for Treatment of Adult Patients With CD19-Positive Mixed Phenotype Acute Leukemia (MPAL)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a multicenter, non-randomized, open-label, phase II study
      evaluating blinatumomab administered subcutaneously in adult subjects
      with CD19+ MPAL.
    explanation: >-
      An active MPAL-specific phase 2 trial of CD19-directed bispecific
      therapy, the investigational context for the CD19-Directed Immunotherapy
      treatment entry and for the lineage-escape risk recorded on the
      plasticity node.
discussions:
- discussion_id: mpal_no_prospective_randomized_therapy_data
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does ALL-directed induction actually outperform AML-directed or hybrid
    induction in mixed phenotype acute leukemia when tested prospectively, and
    for which genetic subgroups?
  attaches_to:
  - treatments#ALL-Type Induction Chemotherapy
  rationale: >-
    Every current recommendation to prefer ALL-type induction derives from
    retrospective series, registry data and meta-analysis of those series. No
    prospective controlled trial has compared induction strategies in MPAL, so
    confounding by indication, era and center cannot be excluded, and the
    optimal approach for genetically defined subgroups is unknown.
  proposed_experiments:
  - experiment_id: exp_mpal_prospective_induction_backbone
    name: Prospective cooperative-group induction-backbone study in centrally reviewed MPAL
    description: >-
      Enrol centrally reviewed WHO/ICC MPAL into a cooperative-group protocol
      that randomizes or risk-stratifies the induction backbone (ALL-type
      versus AML-type versus hybrid), using end-of-induction measurable
      residual disease as the primary early endpoint and event-free survival
      as the confirmatory endpoint.
    decision_criterion: >-
      A prespecified difference in end-of-induction MRD negativity between
      induction backbones, confirmed by event-free survival.
    would_support:
    - >-
        Prospective confirmation that ALL-directed induction is superior would
        convert the current retrospective recommendation into controlled
        evidence.
    would_refute:
    - >-
        Equivalent MRD and survival across backbones would show the retrospective
        signal reflects confounding by indication, era and center.
  - experiment_id: exp_mpal_genetic_subgroup_induction_analysis
    name: Prespecified genetic-subgroup analysis of induction response
    description: >-
      Within the same prospective cohort, analyse induction response separately
      by BCR::ABL1, KMT2A, ZNF384 and BCL11B status and by AML-like versus
      ALL-like methylation class.
    decision_criterion: >-
      A subgroup-by-backbone interaction that survives prespecified
      multiplicity control.
    would_support:
    - >-
        Evidence that induction choice should be genetically rather than
        immunophenotypically guided.
    would_refute:
    - >-
        Absence of interaction would support a single uniform backbone for all
        MPAL.
  evidence:
  - reference: PMID:25605373
    reference_title: How I treat mixed-phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      No prospective, controlled trials exist to guide therapy.
    explanation: >-
      States the absence of prospective controlled evidence directly.
  - reference: PMID:28099272
    reference_title: "Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most data that inform therapy are based on retrospective, uncontrolled
      studies; prospective trials that incorporate targeted approaches based on
      genetics and immunophenotype are needed.
    explanation: >-
      Confirms the evidence base is retrospective and identifies the trial
      design needed to close the gap.
- discussion_id: mpal_aul_optimal_therapy_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the optimal induction strategy for acute undifferentiated leukemia,
    where no lineage is assigned and therefore no lineage-directed regimen is
    indicated by phenotype?
  attaches_to:
  - has_subtypes#Acute undifferentiated leukemia
  rationale: >-
    The therapeutic logic used in MPAL is to pick the regimen matching an
    assignable lineage. In AUL no lineage is assignable, so that logic gives no
    guidance, and population-based data show most AUL patients receive no
    chemotherapy at all and have the worst adult survival of any acute
    leukemia.
  proposed_experiments:
  - experiment_id: exp_aul_molecular_class_registry
    name: Molecular-class-stratified registry study of acute undifferentiated leukemia
    description: >-
      Assemble a prospective registry of centrally reviewed AUL and stratify by
      DNA methylation and transcriptomic class rather than by immunophenotype,
      which by definition provides no lineage information in this entity.
    decision_criterion: >-
      Identification of molecular classes with reproducibly different
      treatment response or survival.
    would_support:
    - >-
        A molecular basis for assigning induction therapy in a phenotypically
        uninformative leukemia.
    would_refute:
    - >-
        Absence of class-associated outcome differences would argue AUL should be
        treated as a single high-risk group.
  - experiment_id: exp_aul_lineage_agnostic_regimen_trial
    name: Trial of lineage-agnostic regimens in prospectively identified AUL
    description: >-
      Evaluate BCL2-directed and other lineage-agnostic regimens in
      prospectively identified AUL, given that most AUL patients currently
      receive no chemotherapy at all.
    decision_criterion: >-
      Response rate and overall survival compared with the population-based
      untreated and chemotherapy-treated AUL benchmarks.
    would_support:
    - >-
        A deliverable standard of care for a group with the worst adult acute
        leukemia survival.
    would_refute:
    - >-
        Lack of activity would redirect effort toward transplant-directed or
        supportive strategies.
  evidence:
  - reference: PMID:41063702
    reference_title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For AUL the optimal therapeutic
      approach is uncertain.
    explanation: >-
      A 2025 review states directly that optimal AUL therapy is undetermined.
  - reference: PMID:31982153
    reference_title: "Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only 35% of AUL patients had received chemotherapy. Comparatively, 94% of
      ALL and 71% of AML cases received chemotherapy.
    explanation: >-
      Shows the practical consequence of the gap: most AUL patients are not
      treated with chemotherapy at all.
- discussion_id: mpal_immunophenotype_does_not_track_genotype
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    If neither genotype nor transcriptome reliably predicts MPAL
    immunophenotype, should MPAL be classified and treated by immunophenotype
    at all, or by epigenetic/transcriptional lineage class?
  attaches_to:
  - pathophysiology#Stem-like Transcriptional State and Epigenetic Lineage Programming
  rationale: >-
    Multiomic single-cell data show immunophenotype is decoupled from genetic
    and transcriptional profile, while methylation-defined AML-like versus
    ALL-like classes predict response to lineage-matched therapy. This
    challenges the immunophenotypic basis of the current WHO/ICC definition
    and of therapy selection.
  proposed_experiments:
  - experiment_id: exp_mpal_methylation_vs_immunophenotype_assignment
    name: Methylation-class-guided versus immunophenotype-guided therapy assignment
    description: >-
      Prospectively assign induction therapy either by the current
      immunophenotypic lineage call or by AML-like versus ALL-like methylation
      class, and compare remission and survival.
    decision_criterion: >-
      Superior complete response or survival in the methylation-guided arm.
    would_support:
    - >-
        Replacing or supplementing the immunophenotypic definition of MPAL with
        an epigenetic one for therapeutic purposes.
    would_refute:
    - >-
        Equivalence would justify retaining immunophenotype as the operational
        basis of classification and therapy.
  - experiment_id: exp_mpal95_independent_validation
    name: Independent validation of the MPAL95 stemness score
    description: >-
      Validate the 95-gene MPAL95 stemness score as a risk stratifier in an
      independent prospective MPAL cohort, modelled jointly with
      end-of-induction measurable residual disease.
    decision_criterion: >-
      MPAL95 retains independent prognostic value after adjustment for MRD and
      established clinical covariates.
    would_support:
    - >-
        Adding a transcriptional stemness axis to MPAL risk stratification.
    would_refute:
    - >-
        Loss of significance after MRD adjustment would show the score is
        captured by existing response-based measures.
  evidence:
  - reference: PMID:39294124
    reference_title: Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that neither genetic profile nor transcriptome reliably correlate
      with specific MPAL immunophenotypes.
    explanation: >-
      Establishes the decoupling of immunophenotype from underlying molecular
      state that motivates the question.
  - reference: PMID:29991687
    reference_title: Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL
      sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated
      with better clinical response when lineage-matched therapy is given.
    explanation: >-
      Provides the alternative epigenetic classification whose clinical value
      the question asks to test prospectively.
references:
- reference: PMID:41063702
  title: "Acute leukemia of ambiguous lineage: the known and the uncertain."
- reference: PMID:35732831
  title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
- reference: PMID:35767897
  title: "International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data."
- reference: PMID:39644014
  title: How to think about acute leukemia of ambiguous lineage.
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
notes: >-
  Scope note: this entry covers the WHO/ICC mixed phenotype acute leukemia
  family (MONDO:0020743) rather than only the narrower legacy term
  "acute biphenotypic leukemia" (MONDO:0020322) cited in issue #7468; the
  latter is retained as a narrowMatch mapping. Acute undifferentiated
  leukemia is curated as a related ambiguous-lineage subtype because it
  shares the immature-progenitor cell of origin and the same diagnostic
  lineage-assignment framework, while assigning no lineage rather than two.

📚

References & Deep Research

References

4

PMID:41063702

Acute leukemia of ambiguous lineage: the known and the uncertain.

No top-level findings curated for this source.

PMID:35732831

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

No top-level findings curated for this source.

PMID:35767897

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

No top-level findings curated for this source.

PMID:39644014

How to think about acute leukemia of ambiguous lineage.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Mixed Phenotype Acute Leukemia: Disease Characteristics Research Report

Edison Scientific Literature 27 citations 2026-07-31T17:10:36.465180

Mixed Phenotype Acute Leukemia: Disease Characteristics Research Report

Scope. This synthesis prioritizes WHO/ICC-era sources and 2023–2024 primary studies. Evidence labels distinguish human cohorts, expert reviews, experimental models, and trial records. DOI links are supplied because the retrieved records did not consistently expose PMIDs; PMIDs are therefore not invented. The data are aggregated disease-level evidence, not individual EHR data.

Executive summary

Mixed phenotype acute leukemia (MPAL) is a rare, aggressive acute leukemia of ambiguous lineage in which the leukemic blasts meet lineage-defining criteria for more than one hematopoietic lineage. B/myeloid MPAL is most common, followed by T/myeloid MPAL. WHO-HAEM5 and the 2022 International Consensus Classification (ICC) combine immunophenotype with genetics and recognize genetically defined groups involving BCR::ABL1, KMT2A, ZNF384, and BCL11B. Current evidence generally favors an ALL-type induction regimen, addition of a tyrosine-kinase inhibitor (TKI) for BCR::ABL1-positive disease, close measurable residual disease (MRD) monitoring, and risk-adapted allogeneic hematopoietic stem-cell transplantation (HSCT), especially in adults. Pediatric patients who clear MRD early can frequently obtain durable remission with ALL therapy without routine HSCT. Recent single-cell studies identify marked inter- and intrapatient heterogeneity but a shared primitive/stem-like state that may explain lineage plasticity, relapse, and lineage switching. (sherban2025acuteleukemiaof pages 12-16, sherban2025acuteleukemiaof pages 20-24, sherban2025acuteleukemiaof pages 1-6, mumme2023singlecellrnasequencing pages 1-2, peretz2024multiomicsinglecell pages 1-2)

Domain	Key facts	Key numbers	Evidence type	Source / DOI / NCT
Definition / classification	Mixed phenotype acute leukemia (MPAL; MONDO:0020743) is an acute leukemia of ambiguous lineage with blasts showing myeloid plus B- or T-lineage features. WHO/ICC-based criteria require lineage-defining markers; B/myeloid is the most common subtype. MPAL with AML-defining recurrent abnormalities such as t(8;21), inv(16), or t(15;17) is excluded from the MPAL category.	ALAL/MPAL represents ~2–3% of acute leukemias; B/myeloid ~67% of MPAL (sherban2025acuteleukemiaof pages 1-6, weinberg2024howtothink pages 5-6)	Classification review + cohort synthesis	Haematologica 2025 doi:10.3324/haematol.2025.287793; Hematology 2024 doi:10.1182/hematology.2024000554 (sherban2025acuteleukemiaof pages 1-6, weinberg2024howtothink pages 5-6)
Epidemiology	MPAL is rare in both children and adults. SEER-based incidence data cited in recent review support extreme rarity; pediatric cohorts show male predominance and substantial Hispanic representation in US series.	Incidence 0.35 per 1,000,000 person-years; pediatric MRD cohort: n=94, 66% male, 55% Hispanic, 46% age <10 years (sherban2025acuteleukemiaof pages 1-6, oberley2020significanceofminimal pages 2-3)	Registry/review + multicenter pediatric cohort	Haematologica 2025 doi:10.3324/haematol.2025.287793; Leukemia 2020 doi:10.1038/s41375-020-0741-0 (sherban2025acuteleukemiaof pages 1-6, oberley2020significanceofminimal pages 2-3)
Molecular subtypes	Recurrent genomic lesions include BCR::ABL1, KMT2A rearrangements, ZNF384 rearrangements, and BCL11B activation; RUNX1 mutations are enriched. B/myeloid and T/myeloid MPAL have different mutational and methylation patterns.	BCR::ABL1 in 15–20%; KMT2A-r ~10%; ZNF384-r up to 50% of pediatric B/myeloid MPAL; BCL11B activation 10–15% overall and up to one-third of T/myeloid MPAL (sherban2025acuteleukemiaof pages 9-12, weinberg2024howtothink pages 5-6)	Genomic cohort + review	Nature 2018 doi:10.1038/s41586-018-0436-0; Nature Communications 2018 doi:10.1038/s41467-018-04924-z; Hematology 2024 doi:10.1182/hematology.2024000554 (sherban2025acuteleukemiaof pages 9-12, weinberg2024howtothink pages 5-6)
Diagnostics	Diagnosis integrates morphology, multiparameter flow cytometry, cytogenetics/FISH, and NGS/RNA fusion testing. Pediatric centrally reviewed cases were predominantly B/myeloid, MPO-positive and CD19-positive. Differential diagnosis includes secondary AML with mixed phenotype, which behaves differently from true MPAL.	Pediatric cohort: 89% B/myeloid, 94% MPO+, 90% CD19+; ALL-directed induction CR 96.6% in MPAL vs 14.3% in secondary AML with mixed phenotype in cited comparative series (oberley2020significanceofminimal pages 2-3, sherban2025acuteleukemiaof pages 6-9)	Multicenter cohort + comparative clinicopathologic study	Leukemia 2020 doi:10.1038/s41375-020-0741-0; Haematologica 2025 doi:10.3324/haematol.2025.287793 (oberley2020significanceofminimal pages 2-3, sherban2025acuteleukemiaof pages 6-9)
First-line therapy	Current expert consensus favors ALL-type induction for most MPAL, with TKI added for Philadelphia-positive/BCR::ABL1-positive disease. Pediatric data support ALL therapy without routine upfront HSCT in many cases.	Meta-analytic effect cited: ALL-based therapy superior for CR and OS (OR 0.33 and 0.45 vs AML-based, direction favoring ALL); pediatric 5-year EFS 80%±4% with ALL-type vs 36%±7.2% with AML-type; HyperCVAD CR/CRi 84% in adults (sherban2025acuteleukemiaof pages 12-16, orgel2020mixed‐phenotypeacuteleukemia pages 1-2)	Review/meta-analysis + pediatric cohort	Haematologica 2025 doi:10.3324/haematol.2025.287793; Cancer 2020 doi:10.1002/cncr.32552 (sherban2025acuteleukemiaof pages 12-16, orgel2020mixed‐phenotypeacuteleukemia pages 1-2)
MRD / HSCT	MRD is a major prognostic marker. In children, early MRD negativity predicts better survival and may support avoiding HSCT in CR1; in adults, HSCT is often considered for high-risk disease, persistent MRD, or adverse genetics.	70% EOI MRD-negative after ALL induction; EOI MRD positivity HR 6.00 for 5-year EFS and HR 9.57 for OS; adult transplant registry: 3-year relapse 31.4%, NRM 22.1%, LFS 46.5%, OS 56.3%; MRD-negative adults after induction had 75.8% vs 45.2% 5-year OS in one study (oberley2020significanceofminimal pages 1-2, sherban2025acuteleukemiaof pages 20-24)	Multicenter pediatric cohort + adult transplant registry/review	Leukemia 2020 doi:10.1038/s41375-020-0741-0; Haematologica 2025 doi:10.3324/haematol.2025.287793 (oberley2020significanceofminimal pages 1-2, sherban2025acuteleukemiaof pages 20-24)
Prognosis	MPAL overall has poorer outcomes than standard-risk ALL and many AML subsets, but prognosis varies by age, genetics, MRD, and therapy. KMT2A-rearranged and complex-karyotype disease are adverse; Ph+ disease outcomes improve with TKI-based therapy.	Pediatric COG cohort: 5-year EFS 72%±8%, OS 77%±7%; ALL-only/no HSCT subgroup EFS 75%±13%, OS 84%±11%; Ph+ MPAL median OS 53.6 months, 5-year OS 49%; AUL median OS 1.4 months; KMT2A-r associated with ~10-fold increased mortality risk in cited review (orgel2020mixed‐phenotypeacuteleukemia pages 1-2, sherban2025acuteleukemiaof pages 12-16)	Pediatric cohort + review synthesis	Cancer 2020 doi:10.1002/cncr.32552; Haematologica 2025 doi:10.3324/haematol.2025.287793 (orgel2020mixed‐phenotypeacuteleukemia pages 1-2, sherban2025acuteleukemiaof pages 12-16)
Recent single-cell developments	Recent 2023–2024 single-cell studies show MPAL is highly heterogeneous yet shares stem-like programs. Pediatric scRNA-seq distinguished B/myeloid from T/myeloid MPAL; adult multiomic single-cell profiling identified a stem-like transcriptional state and a prognostic MPAL95 score.	Pediatric scRNA-seq: >40,000 cells from 9 cases; 44% relapsed/refractory overall in that cohort; adult multiomic study: 14 newly diagnosed cases; MPAL95 predicted survival in an independent cohort (mumme2023singlecellrnasequencing pages 1-2, peretz2024multiomicsinglecell pages 1-2)	Primary single-cell / multiomic studies	Genome Medicine 2023 doi:10.1186/s13073-023-01241-z; Nature Communications 2024 doi:10.1038/s41467-024-52317-2 (mumme2023singlecellrnasequencing pages 1-2, peretz2024multiomicsinglecell pages 1-2)
Experimental / translational trials	Active/modern trials are testing lower-intensity or targeted strategies, especially for adults or newly diagnosed disease: blinatumomab for CD19+ MPAL, venetoclax/azacitidine-based combinations, and other investigational regimens. Preclinical ZNF384 models support FLT3 inhibition.	NCT07222579 recruiting (subcutaneous blinatumomab; adult CD19+ MPAL; planned enrollment 78); NCT07517510 phase 2 enrolling by invitation (homoharringtonine + venetoclax + azacitidine; enrollment 40); NCT07573670 phase 2 not yet recruiting (BCL-2 inhibitor + azacitidine; enrollment 52); ZNF384 study tested 71 leukemia samples plus 15 MPAL samples and showed gilteritinib activity in PDX models (NCT07222579 chunk 3, NCT07517510 chunk 1, NCT07573670 chunk 2, dickerson2022znf384fusiononcoproteins pages 15-15)	Clinical trials + preclinical functional study	ClinicalTrials.gov NCT07222579, NCT07517510, NCT07573670; Blood Cancer Discovery 2022 doi:10.1158/2643-3230.bcd-21-0163 (NCT07222579 chunk 3, NCT07517510 chunk 1, NCT07573670 chunk 2, dickerson2022znf384fusiononcoproteins pages 15-15)

Table: Concise knowledge-base summary table for mixed phenotype acute leukemia covering classification, epidemiology, molecular features, diagnostics, treatment, prognosis, and recent translational developments. It highlights key numbers and cites the available evidence contexts and trial identifiers for rapid downstream curation.

1. Disease information

Definition and classification

MPAL belongs to the category acute leukemia of ambiguous lineage (ALAL). Unlike acute undifferentiated leukemia, MPAL has convincing evidence of commitment to at least two lineages. Disease may be:

Biphenotypic: one blast population co-expresses lineage-defining markers.
Bilineal/trilineal: two or more immunophenotypically discrete blast populations together constitute the acute leukemia; bilineal disease may have inferior outcomes.
Phenotypic groups: B/myeloid (approximately 67%), T/myeloid, rare B/T, B/T/myeloid, or T/megakaryoblastic disease. (sherban2025acuteleukemiaof pages 6-9, sherban2025acuteleukemiaof pages 1-6)

WHO/ICC exclude cases whose mixed immunophenotype occurs in an otherwise defining AML entity, including AML with t(8;21)/RUNX1::RUNX1T1, inv(16)/CBFB::MYH11, or t(15;17)/PML::RARA. Therapy-related or secondary AML with aberrant lymphoid markers must likewise be separated from genuine MPAL. (sherban2025acuteleukemiaof pages 6-9, weinberg2024howtothink pages 5-6)

Identifiers and synonyms

MONDO: MONDO:0020743.
Parent concept: acute leukemia of ambiguous lineage, MONDO:0019460.
Synonyms: mixed-phenotype acute leukemia, mixed phenotype acute leukaemia, MPAL, biphenotypic acute leukemia, bilineal acute leukemia, mixed-lineage acute leukemia. “Biphenotypic leukemia” is historical and should not be treated as exactly synonymous in modern classification.
MeSH/OMIM/Orphanet: no reliably verified MPAL-specific identifiers were exposed by the retrieved primary records. MPAL is a somatic cancer category rather than a classic single-gene Mendelian OMIM disorder.
ICD: ICD-10-CM lacks a robust phenotype-specific MPAL code and cases are commonly mapped under acute leukemia/acute leukemia of ambiguous cell type according to local coding rules; ICD-11 classification should be verified against the deploying jurisdiction’s current release.

Open Targets independently maps MPAL to MONDO:0020743 and identifies clinically relevant lineage targets CD19 and the CD3 complex; this is target-association evidence, not proof that these genes cause MPAL. (OpenTargets Search: mixed phenotype acute leukemia)

2. Etiology, risk, and protective factors

MPAL is predominantly a sporadic clonal somatic malignancy. Its proximate causes are acquired driver rearrangements/mutations and epigenetic dysregulation in a hematopoietic stem or early progenitor cell capable of multilineage differentiation. There is no single necessary causal gene.

Genetic drivers: BCR::ABL1, KMT2A rearrangements, ZNF384 fusions, and BCL11B activation are the best-established recurrent lesions. Cooperating alterations affect RUNX1, WT1, ETV6, CEBPA, FLT3/JAK–STAT, RAS, IKZF1, and PAX5, among others. (sherban2025acuteleukemiaof pages 9-12, weinberg2024howtothink pages 5-6)
Age: KMT2A-rearranged disease is enriched in infants/children; BCR::ABL1-positive B/myeloid MPAL is enriched in older patients. ZNF384-rearranged disease is particularly prominent in pediatric B/myeloid MPAL. (sherban2025acuteleukemiaof pages 9-12)
Secondary disease: prior myelodysplasia, cytotoxic therapy, or an AML-type mutation pattern should raise concern for secondary AML with mixed phenotype rather than de novo MPAL. In one comparison, secondary AML with mixed phenotype had median overall survival of 10.3 months versus 42.8 months for MPAL and responded very differently to ALL induction. (sherban2025acuteleukemiaof pages 6-9)

No MPAL-specific, reproducible associations with smoking, alcohol, diet, infection, occupation, pollution, or a defined gene–environment interaction were identified. General leukemia risks such as ionizing radiation and prior cytotoxic therapy should not be automatically annotated as MPAL-specific causes. No validated genetic or environmental protective factors are known. These are evidence gaps, not demonstrations that such effects cannot exist.

3. Phenotypes

MPAL has an acute, severe, progressive presentation at any age. Clinical manifestations largely result from marrow replacement and tissue infiltration rather than from the mixed immunophenotype itself.

Phenotype	Type and usual behavior	Suggested HPO term
Anemia, fatigue, pallor, dyspnea	Laboratory abnormality/symptom; common, variable severity	Anemia (HP:0001903), Fatigue (HP:0012378), Pallor (HP:0000980)
Thrombocytopenia, bruising, bleeding/petechiae	Laboratory/sign; may become life-threatening	Thrombocytopenia (HP:0001873), Abnormal bleeding (HP:0001892), Petechiae (HP:0000967)
Neutropenia, fever, recurrent/severe infection	Laboratory/symptom; fluctuates and worsens with chemotherapy	Neutropenia (HP:0001875), Fever (HP:0001945), Recurrent infections (HP:0002719)
Leukocytosis or circulating blasts	Laboratory abnormality; variable	Leukocytosis (HP:0001974), Abnormality of leukocytes (HP:0001881)
Bone pain	Symptom, particularly in children	Bone pain (HP:0002653)
Hepatosplenomegaly/lymphadenopathy	Clinical signs of infiltration	Hepatomegaly (HP:0002240), Splenomegaly (HP:0001744), Lymphadenopathy (HP:0002716)
CNS involvement	Complication at diagnosis or relapse; uncommon but clinically important	Abnormality of the central nervous system (HP:0002011)
Mixed-lineage blast phenotype	Defining laboratory/pathology feature	No single adequate HPO term; encode with pathology/NCIT plus marker findings

A 94-patient pediatric cohort was 89% B/myeloid, 94% MPO-positive, and 90% CD19-positive; 70% had presenting leukocytes below 50,000/µL and 68% were CNS1. These figures describe one US cohort rather than universal frequencies. (oberley2020significanceofminimal pages 2-3)

Quality of life. MPAL-specific EQ-5D, SF-36, PROMIS, or utility studies were not identified. Expected impacts include hospitalization, infection isolation, transfusion dependence, treatment toxicity, impaired schooling/work, fertility concerns, and psychological burden, but these should be labeled extrapolations from acute leukemia care rather than MPAL-specific measured effects.

4. Genetic and molecular information

Recurrent somatic lesions

BCR::ABL1: approximately 15–20%, usually B/myeloid and enriched with increasing age. It encodes a constitutively active ABL tyrosine kinase and is therapeutically actionable with a TKI. (sherban2025acuteleukemiaof pages 9-12)
KMT2A rearrangement: approximately 10%; enriched in infants and younger children, usually B/myeloid, and associated with especially poor prognosis. (sherban2025acuteleukemiaof pages 12-16, sherban2025acuteleukemiaof pages 9-12)
ZNF384 rearrangement: reported in up to 50% of pediatric B/myeloid MPAL but uncommon in adult MPAL. Fusion partners include EP300, CREBBP, TCF3, and others. (sherban2025acuteleukemiaof pages 9-12)
BCL11B activation/rearrangement: about 10–15% of MPAL overall and up to one-third of T/myeloid MPAL; it links T/myeloid MPAL biologically to early T-cell precursor ALL. (sherban2025acuteleukemiaof pages 9-12, weinberg2024howtothink pages 5-6)
Other alterations: T/myeloid disease has relatively high mutation burden involving WT1, ETV6, RUNX1, CEBPA, FLT3 and JAK–STAT signaling; B/myeloid disease more often has IKZF1, PAX5, and RAS-pathway lesions. Complex karyotype is adverse. (sherban2025acuteleukemiaof pages 9-12)

These are somatic structural variants or somatic sequence variants in the leukemia clone. Population allele frequencies in gnomAD are therefore generally not meaningful for the defining fusions. Patient-specific germline testing is appropriate when age, personal/family history, or the variant allele pattern suggests an inherited leukemia-predisposition syndrome; MPAL itself does not have a defined Mendelian inheritance pattern.

Epigenetics and functional consequence

Adult integrative profiling separated MPAL into AML-like and ALL-like DNA-methylation groups; lineage-matched therapy produced complete response in 72% versus 22% with molecularly mismatched treatment, supporting a biological rather than merely descriptive role for epigenetic lineage state. Genetically similar blast compartments can display different phenotypes, indicating that epigenetic regulation contributes substantially to lineage ambiguity. (sherban2025acuteleukemiaof pages 12-16, sherban2025acuteleukemiaof pages 9-12)

In ZNF384-rearranged experimental systems, fusion proteins occupy enhancer/intragenic regions, increase H3 lysine acetylation, deregulate stem-cell transcription factors, skew HSPCs toward myeloid differentiation, and promote self-renewal. The study’s abstract states that the fusions “promote hematopoietic expansion, myeloid lineage skewing, and self-renewal.” NRAS^G12D or another cooperating proliferative lesion was required for fully penetrant leukemia in mouse HSPCs, whereas human HSPCs developed B/myeloid leukemia. (dickerson2022znf384fusiononcoproteins pages 15-15)

5. Environmental and infectious information

There is no established MPAL-specific infectious agent, toxin, dietary exposure, exercise pattern, alcohol association, or smoking association. MPAL is not contagious. Prior chemotherapy/radiotherapy may precede secondary myeloid disease with mixed marker expression, but rigorous distinction from de novo MPAL is essential. No validated MPAL-specific chemopreventive or lifestyle intervention exists.

6. Mechanism and pathophysiology

Causal chain

Upstream initiation: an acquired rearrangement or mutation occurs in a multipotent HSPC or early progenitor.
Lineage-program disruption: fusion oncoproteins or transcription-factor dysregulation alter enhancer use, chromatin state, and lineage-specifying transcription.
Cooperating proliferation/survival signaling: RAS, FLT3, JAK–STAT, ABL1, or related lesions increase survival and expansion.
Stemness and plasticity: the clone retains multilineage differentiation potential, generating biphenotypic or bilineal blast compartments.
Marrow/tissue expansion: blasts suppress normal erythropoiesis, granulopoiesis, and megakaryopoiesis, producing anemia, infection, bleeding, and tissue infiltration.
Treatment selection: lineage-targeted therapy can select phenotypically distinct subclones or promote lineage switch; persistent stem-like/MRD compartments seed relapse. (sherban2025acuteleukemiaof pages 9-12, mumme2023singlecellrnasequencing pages 1-2, peretz2024multiomicsinglecell pages 1-2, dickerson2022znf384fusiononcoproteins pages 15-15)

Molecular profiling and advanced technologies

The 2023 pediatric scRNA-seq study analyzed >40,000 cells from nine marrow samples. B/myeloid and T/myeloid MPAL had distinct signatures; both overexpressed MAP2K2 and CD81, while HBEGF marked B/myeloid and PTEN marked T/myeloid disease. T/myeloid MPAL overlapped strongly with early T-cell precursor ALL, and relapsed samples showed IL-16-pathway upregulation. The abstract concludes that the subtypes have “distinct scRNAseq profiles from each other, AML, and ALL.” (mumme2023singlecellrnasequencing pages 1-2)

A September 2024 adult multiomic study profiled 14 newly diagnosed patients and found that genotype or transcriptome did not reliably predict immunophenotype. A shared primitive transcriptional state correlated with differentiation potential and poorer survival; its 95-gene MPAL95 score predicted survival in an independent bulk-RNA cohort. The authors’ central conclusion was that MPAL blasts express a “shared stem cell-like transcriptional profile indicative of high differentiation potential.” (peretz2024multiomicsinglecell pages 1-2)

Suggested annotations include GO:0030097 hemopoiesis, GO:0045165 cell fate commitment, GO:0008283 cell population proliferation, GO:0007049 cell cycle, GO:0043066 negative regulation of apoptotic process, GO:0045595 regulation of cell differentiation, GO:0006355 regulation of transcription, and GO:0040029 regulation of gene expression, epigenetic. Relevant cell types include hematopoietic stem cell, hematopoietic multipotent progenitor, lymphoid progenitor, myeloid progenitor, B-lineage lymphoblast, T-lineage lymphoblast, and myeloblast; exact CL identifiers should be ontology-release validated before production ingestion.

7. Anatomical structures affected

Primary: bone marrow (UBERON:0002371), peripheral blood, and hematopoietic/lymphoid system.
Secondary: spleen (UBERON:0002106), liver (UBERON:0002107), lymph nodes (UBERON:0000029), CNS, skin, and other extramedullary sites.
Cellular: leukemic HSPC/progenitor and its phenotypically diverse blast descendants.
Subcellular: nucleus and chromatin for transcription-factor fusions; cytoplasm/membrane for lineage markers; cytoplasmic and nuclear tyrosine-kinase signaling for BCR::ABL1.
Lateralization: not applicable.

Non-leukemic pediatric MPAL/lymphoma can occur in lymph node, skin, or other extranodal sites. In one prospective series, 11 such cases were found among 146 lymphoblastic lymphomas; all entered complete remission on a lymphoblastic lymphoma protocol. (martin‐guerrero2019non‐leukemicpediatricmixed pages 1-4, martin‐guerrero2019non‐leukemicpediatricmixed pages 16-17)

8. Temporal development

Onset is acute, developing over days to weeks clinically, although somatic evolution precedes symptoms. It occurs from infancy through old age. Untreated disease is rapidly progressive and not self-limited. Clinical phases are diagnosis, induction, remission/MRD assessment, consolidation/maintenance, and either durable remission or relapse/refractory disease; conventional solid-tumor AJCC staging is not applicable.

The key intervention window is induction and early MRD clearance. In children, end-of-induction MRD positivity was strongly associated with inferior 5-year EFS (HR 6.00) and OS (HR 9.57). Relapse can preserve phenotype, become more homogeneous, or undergo lineage switch. (oberley2020significanceofminimal pages 1-2)

9. Inheritance, epidemiology, and population

ALAL/MPAL represents approximately 2–3% of acute leukemias; a recent review cited a SEER incidence of approximately 0.35 per million person-years. Broader publications have reported 1–5%, reflecting changes in diagnostic criteria and referral populations. (orgel2020mixed‐phenotypeacuteleukemia pages 1-2, sherban2025acuteleukemiaof pages 1-6)

A nine-case pediatric single-cell cohort had mean age 13.4 years and was 78% male, whereas the larger 94-patient US cohort was 66% male and 55% Hispanic. These observations do not establish a biological ethnic predisposition and may reflect ascertainment and center demographics. (mumme2023singlecellrnasequencing pages 4-5, oberley2020significanceofminimal pages 2-3)

There is no standard autosomal-dominant, autosomal-recessive, X-linked, mitochondrial, founder, carrier-frequency, anticipation, or germline-mosaicism model for MPAL. Penetrance and carrier frequency are therefore not applicable at the disease level. Germline predisposition should be recorded separately when demonstrated.

10. Diagnostics

Recommended workflow

CBC, differential, peripheral smear, coagulation and tumor-lysis chemistry.
Bone-marrow aspirate/core biopsy for morphology and blast burden.
Multiparameter flow cytometry with intensity compared with normal counterparts and assessment for one versus multiple blast populations.
Karyotype and FISH, including BCR::ABL1 and KMT2A; add probes guided by phenotype.
Broad DNA NGS plus RNA fusion sequencing, because cryptic ZNF384/BCL11B and kinase fusions may be missed by karyotype or limited panels.
HLA typing and baseline organ assessment if HSCT is plausible.
MRD assay design at diagnosis, preserving all abnormal compartments and considering fusion-specific PCR/NGS where validated.

Lineage-defining criteria

Myeloid: myeloperoxidase (MPO), or monocytic differentiation supported by at least two markers such as CD11c, CD14, CD64, lysozyme, or nonspecific esterase.
T lineage: strong surface or cytoplasmic CD3; recent guidance uses intensity greater than 50% of mature T-cell levels.
B lineage: strong CD19 plus appropriate additional B markers; recent guidance compares intensity with normal B-cell progenitors.
Acute disease generally requires an aggregate ≥20% blasts, while genetically defined entities and classification-specific exceptions require careful WHO/ICC application. (sherban2025acuteleukemiaof pages 6-9, sherban2025acuteleukemiaof pages 1-6)

Differential diagnosis

Exclude AML with defining recurrent genetics, B-ALL or T-ALL with aberrant myeloid antigen expression, early T-cell precursor ALL, AML with minimal differentiation, acute megakaryoblastic leukemia, secondary/therapy-related AML, blast-phase CML, myeloid/lymphoid neoplasms with eosinophilia and kinase rearrangement, and acute undifferentiated leukemia. Merely expressing CD13, CD33, CD7, or another cross-lineage antigen is insufficient for MPAL.

No population, newborn, prenatal, carrier, or asymptomatic screening is recommended. WES/WGS may help unresolved cases but does not replace flow cytometry and RNA fusion detection. Mitochondrial or repeat-expansion testing is not relevant.

11. Outcome and prognosis

In a centrally reviewed Children’s Oncology Group cohort, 5-year EFS was 72%±8% and OS 77%±7%. Children treated with ALL chemotherapy alone without HSCT had 5-year EFS 75%±13% and OS 84%±11%, although selection bias limits causal interpretation. (orgel2020mixed‐phenotypeacuteleukemia pages 1-2)

In an adult transplant registry of 519 MPAL patients, 3-year relapse was 31.4%, non-relapse mortality 22.1%, leukemia-free survival 46.5%, and OS 56.3%. Another adult series reported 5-year OS of 54% after transplantation; MRD-negative patients had 75.8% versus 45.2% survival. (sherban2025acuteleukemiaof pages 20-24)

Adverse factors include older age, complex karyotype, KMT2A rearrangement, secondary AML-type biology, induction failure, and persistent MRD. BCR::ABL1-positive prognosis has improved substantially with TKI therapy; one synthesis reported median OS 53.6 months and 5-year OS 49%. (sherban2025acuteleukemiaof pages 12-16, sherban2025acuteleukemiaof pages 9-12)

Major complications include bacterial/fungal infection, hemorrhage, tumor lysis, leukostasis, organ toxicity, infertility, graft-versus-host disease, relapse, and lineage switch. MPAL-specific long-term disability and quality-of-life statistics remain sparse.

12. Treatment

Current strategy

ALL-type induction is generally preferred over AML or hybrid induction. A synthesis found superior complete remission and OS with ALL therapy; pediatric 5-year EFS was reported as 80%±4% with ALL-type versus 36%±7.2% with AML-type therapy. Hyper-CVAD produced CR/CRi in 84% in an adult series. (sherban2025acuteleukemiaof pages 12-16)
BCR::ABL1-positive MPAL: add an ABL TKI (e.g., imatinib, dasatinib, ponatinib selected by patient and mutation context) promptly.
MRD-adapt therapy: repeat flow and/or molecular MRD after induction and consolidation. Pediatric end-of-induction MRD negativity below 0.01% occurred in 70% and strongly predicted favorable outcome. (oberley2020significanceofminimal pages 1-2)
HSCT: not routinely necessary for every pediatric patient who clears MRD; consider in adults, persistent MRD, induction failure, adverse genetics, or relapse. Conditioning choice and comorbidity must be individualized. (sherban2025acuteleukemiaof pages 20-24)
Relapse/targeted therapy: CD19-positive disease may receive blinatumomab; CD19/CD22-targeted antibodies or CAR-T approaches are biologically plausible but can select lineage-negative or switched clones. Venetoclax-based therapy is investigational. ZNF384-rearranged preclinical models suggest FLT3 inhibition. (dickerson2022znf384fusiononcoproteins pages 15-15, NCT07222579 chunk 3)

Suggested NCIT concepts include acute lymphoblastic leukemia chemotherapy regimen, hyper-CVAD regimen, tyrosine kinase inhibitor therapy, blinatumomab, chimeric antigen receptor T-cell therapy, allogeneic hematopoietic stem-cell transplantation, measurable residual disease assessment, venetoclax, azacitidine, and supportive transfusion therapy; exact NCIT codes should be release validated.

Current trials and real-world implementation

NCT05327894 (Interfant-21): recruiting phase 3 protocol for infants with KMT2A-rearranged ALL or MPAL; target enrollment 160. Open Targets links this trial to CD19/CD3-relevant MPAL biology. (OpenTargets Search: mixed phenotype acute leukemia)
NCT04872478: recruiting phase 1 MRX-2843 study in adolescent/adult relapsed or refractory AML, ALL, or MPAL; target enrollment 50.
NCT07222579: recruiting subcutaneous blinatumomab study for adult CD19-positive MPAL, including chemotherapy-ineligible, MRD-positive, and relapsed/refractory cohorts. (NCT07222579 chunk 3)
NCT07517510: phase 2 HVA—homoharringtonine, venetoclax, and azacitidine—for newly diagnosed adult MPAL; planned n=40, with 2026 start. (NCT07517510 chunk 1)
NCT07573670: phase 2 BCL-2 inhibitor plus azacitidine for newly diagnosed BCR::ABL1-negative MPAL; planned n=52. (NCT07573670 chunk 2)
NCT02135874: completed phase 2 hybrid clofarabine/idarubicin/cytarabine/vincristine/dexamethasone study, illustrating prior attempts to cover both myeloid and lymphoid biology. (NCT02135874 chunk 2)

These trials are investigational and do not establish efficacy. Supportive care follows acute leukemia standards: tumor-lysis prophylaxis, antimicrobial prophylaxis, irradiated/leukoreduced blood products, fertility preservation, nutrition, psychosocial care, and rehabilitation after deconditioning.

13. Prevention

No MPAL-specific primary prevention, vaccine, screening program, prophylactic medication, or validated behavioral intervention exists. Sensible measures include minimizing unnecessary ionizing radiation and carcinogenic exposure and following survivors of prior cytotoxic therapy according to established oncology guidance, but there is no evidence that these measures specifically prevent MPAL.

Secondary prevention is limited to prompt evaluation of unexplained cytopenias, leukocytosis, bruising, infection, or constitutional symptoms; routine screening of asymptomatic people is not justified by the very low incidence. Tertiary prevention includes infection and tumor-lysis prophylaxis, MRD-guided relapse prevention, vaccination planning after chemotherapy/HSCT, and survivorship surveillance. Genetic counseling is indicated only where a separate germline predisposition is suspected or demonstrated.

14. Other species and natural disease

No well-defined, naturally occurring veterinary disease that is taxonomically equivalent to human WHO/ICC MPAL was identified. Dogs, cats, and other animals can develop leukemias with ambiguous immunophenotypes, but diagnostic comparability and recurrent molecular drivers are insufficient to annotate these as the same disease. MPAL is not infectious or zoonotic, and cross-species transmission is not applicable.

15. Model organisms and experimental systems

The strongest disease models are molecularly engineered systems rather than spontaneous animal disease:

EP300::Znf384 knock-in mouse and virally transduced mouse HSPCs: reproduce progenitor expansion, myeloid skewing, and self-renewal; a cooperating NRAS^G12D lesion was required for fully penetrant leukemia. Limitation: engineered genotype and murine hematopoiesis do not reproduce all human MPAL heterogeneity. (dickerson2022znf384fusiononcoproteins pages 15-15)
Human CD34+ HSPCs expressing ZNF384 fusion: generate B/myeloid leukemia and more directly model human lineage ambiguity. (dickerson2022znf384fusiononcoproteins pages 15-15)
Patient-derived xenografts: preserve aspects of human clone biology and support drug testing. A ZNF384-rearranged xenograft showed marked in-vivo response to the FLT3 inhibitor gilteritinib. Limitation: immunodeficient recipients cannot model an intact immune microenvironment. (dickerson2022znf384fusiononcoproteins pages 15-15)
Primary single-cell datasets: pediatric scRNA-seq and adult DNA/RNA/protein multiomics resolve intratumoral states but are observational and based on nine and 14 patients, respectively. (mumme2023singlecellrnasequencing pages 1-2, peretz2024multiomicsinglecell pages 1-2)

Relevant species are Homo sapiens (NCBI Taxon 9606) and Mus musculus (NCBI Taxon 10090). Useful resources include MGI/IMSR for engineered mice, Cellosaurus for cell models, and GEO/SRA for transcriptomic datasets.

Evidence limitations and expert interpretation

The central uncertainty is not whether MPAL exists, but how best to define and treat its biologically diverse forms. Diagnostic criteria have changed repeatedly, sample sizes are small, and adult and pediatric disease differ. The most defensible current interpretation is that MPAL comprises several genomic diseases converging on early-progenitor lineage plasticity, not one uniform cancer. This explains why immunophenotype alone is an imperfect treatment guide and why integrated flow cytometry, fusion testing, mutation profiling, epigenetic/transcriptomic characterization, and MRD are increasingly important. The 2024 single-cell data are promising for risk stratification, but MPAL95 and methylation-guided therapy require prospective validation before routine implementation. (sherban2025acuteleukemiaof pages 9-12, weinberg2024howtothink pages 5-6, peretz2024multiomicsinglecell pages 1-2)

Key source URLs and publication dates

Weinberg, Hematology, December 2024: https://doi.org/10.1182/hematology.2024000554. (weinberg2024howtothink pages 5-6)
Peretz et al., Nature Communications, September 2024: https://doi.org/10.1038/s41467-024-52317-2. (peretz2024multiomicsinglecell pages 1-2)
Mumme et al., Genome Medicine, October 2023: https://doi.org/10.1186/s13073-023-01241-z. (mumme2023singlecellrnasequencing pages 1-2)
Dickerson et al., Blood Cancer Discovery, March 2022: https://doi.org/10.1158/2643-3230.bcd-21-0163. (dickerson2022znf384fusiononcoproteins pages 15-15)
Orgel et al., Cancer, 2020: https://doi.org/10.1002/cncr.32552. (orgel2020mixed‐phenotypeacuteleukemia pages 1-2)
Oberley et al., Leukemia, February 2020: https://doi.org/10.1038/s41375-020-0741-0. (oberley2020significanceofminimal pages 1-2)
Alexander et al., Nature, September 2018: https://doi.org/10.1038/s41586-018-0436-0. (sherban2025acuteleukemiaof pages 9-12)
Takahashi et al., Nature Communications, July 2018: https://doi.org/10.1038/s41467-018-04924-z. (sherban2025acuteleukemiaof pages 9-12)

References

(sherban2025acuteleukemiaof pages 12-16): Adi Sherban and Ofir Wolach. Acute leukemia of ambiguous lineage: the known and the uncertain. Haematologica, 111:813-827, Oct 2025. URL: https://doi.org/10.3324/haematol.2025.287793, doi:10.3324/haematol.2025.287793. This article has 3 citations.
(sherban2025acuteleukemiaof pages 20-24): Adi Sherban and Ofir Wolach. Acute leukemia of ambiguous lineage: the known and the uncertain. Haematologica, 111:813-827, Oct 2025. URL: https://doi.org/10.3324/haematol.2025.287793, doi:10.3324/haematol.2025.287793. This article has 3 citations.
(sherban2025acuteleukemiaof pages 1-6): Adi Sherban and Ofir Wolach. Acute leukemia of ambiguous lineage: the known and the uncertain. Haematologica, 111:813-827, Oct 2025. URL: https://doi.org/10.3324/haematol.2025.287793, doi:10.3324/haematol.2025.287793. This article has 3 citations.
(mumme2023singlecellrnasequencing pages 1-2): Hope L. Mumme, Sunil S. Raikar, Swati S. Bhasin, Beena E. Thomas, Taylor Lawrence, Elizabeth P. Weinzierl, Yakun Pang, Deborah DeRyckere, Chuck Gawad, Daniel S. Wechsler, Christopher C. Porter, Sharon M. Castellino, Douglas K. Graham, and Manoj Bhasin. Single-cell rna sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia. Genome Medicine, Oct 2023. URL: https://doi.org/10.1186/s13073-023-01241-z, doi:10.1186/s13073-023-01241-z. This article has 20 citations and is from a highest quality peer-reviewed journal.
(peretz2024multiomicsinglecell pages 1-2): Cheryl A. C. Peretz, Vanessa E. Kennedy, Anushka Walia, Cyrille L. Delley, Andrew Koh, Elaine Tran, Iain C. Clark, Corey E. Hayford, Chris D’Amato, Yi Xue, Kristina M. Fontanez, Aaron A. May-Zhang, Trinity Smithers, Yigal Agam, Qian Wang, Hai-ping Dai, Ritu Roy, Aaron C. Logan, Alexander E. Perl, Adam Abate, Adam Olshen, and Catherine C. Smith. Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-52317-2, doi:10.1038/s41467-024-52317-2. This article has 24 citations and is from a highest quality peer-reviewed journal.
(weinberg2024howtothink pages 5-6): Olga K. Weinberg. How to think about acute leukemia of ambiguous lineage. Hematology, 2024:287-292, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000554, doi:10.1182/hematology.2024000554. This article has 16 citations and is from a peer-reviewed journal.
(oberley2020significanceofminimal pages 2-3): Matthew J. Oberley, Sunil S. Raikar, Gerald B. Wertheim, Jemily Malvar, Richard Sposto, Karen R. Rabin, Jyotinder N. Punia, Alix E. Seif, Viviane C. Cahen, Reuven J. Schore, Dragos C. Luca, Terri Guinipero, William G. Woods, Maurice R. G. O’Gorman, and Etan Orgel. Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multi-center cohort study. Leukemia, 34:1741-1750, Feb 2020. URL: https://doi.org/10.1038/s41375-020-0741-0, doi:10.1038/s41375-020-0741-0. This article has 28 citations and is from a highest quality peer-reviewed journal.
(sherban2025acuteleukemiaof pages 9-12): Adi Sherban and Ofir Wolach. Acute leukemia of ambiguous lineage: the known and the uncertain. Haematologica, 111:813-827, Oct 2025. URL: https://doi.org/10.3324/haematol.2025.287793, doi:10.3324/haematol.2025.287793. This article has 3 citations.
(sherban2025acuteleukemiaof pages 6-9): Adi Sherban and Ofir Wolach. Acute leukemia of ambiguous lineage: the known and the uncertain. Haematologica, 111:813-827, Oct 2025. URL: https://doi.org/10.3324/haematol.2025.287793, doi:10.3324/haematol.2025.287793. This article has 3 citations.
(orgel2020mixed‐phenotypeacuteleukemia pages 1-2): Etan Orgel, Thomas B. Alexander, Brent L. Wood, Samir B. Kahwash, Meenakshi Devidas, Yunfeng Dai, Todd A. Alonzo, Charles G. Mullighan, Hiroto Inaba, Stephen P. Hunger, Elizabeth A. Raetz, Alan S. Gamis, Karen R. Rabin, Andrew J. Carroll, Nyla A. Heerema, Jason N. Berman, William G. Woods, Mignon L. Loh, Patrick A. Zweidler‐McKay, and John T. Horan. Mixed‐phenotype acute leukemia: a cohort and consensus research strategy from the children’s oncology group acute leukemia of ambiguous lineage task force. Cancer, 126:593-601, Oct 2020. URL: https://doi.org/10.1002/cncr.32552, doi:10.1002/cncr.32552. This article has 79 citations and is from a domain leading peer-reviewed journal.
(oberley2020significanceofminimal pages 1-2): Matthew J. Oberley, Sunil S. Raikar, Gerald B. Wertheim, Jemily Malvar, Richard Sposto, Karen R. Rabin, Jyotinder N. Punia, Alix E. Seif, Viviane C. Cahen, Reuven J. Schore, Dragos C. Luca, Terri Guinipero, William G. Woods, Maurice R. G. O’Gorman, and Etan Orgel. Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multi-center cohort study. Leukemia, 34:1741-1750, Feb 2020. URL: https://doi.org/10.1038/s41375-020-0741-0, doi:10.1038/s41375-020-0741-0. This article has 28 citations and is from a highest quality peer-reviewed journal.
(NCT07222579 chunk 3): Ashkan Emadi, MD PHD. Subcutaneous Blinatumomab for Treatment of Adult Patients With CD19-Positive Mixed Phenotype Acute Leukemia (MPAL). West Virginia University. 2026. ClinicalTrials.gov Identifier: NCT07222579
(NCT07517510 chunk 1): Qing Zhang. HVA in the Treatment of Mixed-Phenotype Acute Leukemia(MPAL).. Guangdong Second Provincial General Hospital. 2026. ClinicalTrials.gov Identifier: NCT07517510
(NCT07573670 chunk 2): Chen Suning. A Phase 2 Study of Bcl-2 Inhibitor Combined With Azacitidine for Newly Diagnosed Mixed Phenotype Acute Leukemia. The First Affiliated Hospital of Soochow University. 2026. ClinicalTrials.gov Identifier: NCT07573670
(dickerson2022znf384fusiononcoproteins pages 15-15): Kirsten M. Dickerson, Chunxu Qu, Qingsong Gao, Ilaria Iacobucci, Zhaohui Gu, Hiroki Yoshihara, Emily A. Backhaus, Yunchao Chang, Laura J. Janke, Beisi Xu, Gang Wu, Evangelia K. Papachristou, Clive S. D'Santos, Kathryn G. Roberts, and Charles G. Mullighan. Znf384 fusion oncoproteins drive lineage aberrancy in acute leukemia. Blood cancer discovery, 3:240-263, Mar 2022. URL: https://doi.org/10.1158/2643-3230.bcd-21-0163, doi:10.1158/2643-3230.bcd-21-0163. This article has 46 citations and is from a peer-reviewed journal.
(OpenTargets Search: mixed phenotype acute leukemia): Open Targets Query (mixed phenotype acute leukemia, 10 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(martin‐guerrero2019non‐leukemicpediatricmixed pages 1-4): Idoia Martin‐Guerrero, Itziar Salaverria, Birgit Burkhardt, Catherine Chassagne‐Clement, Monika Szczepanowski, Susanne Bens, Wolfram Klapper, Martin Zimmermann, Edita Kabickova, Yves Bertrand, Alfred Reiter, Reiner Siebert, and Ilske Oschlies. Non‐leukemic pediatric mixed phenotype acute leukemia/lymphoma: genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma. Genes, Chromosomes and Cancer, 58(6):365-372, Jan 2019. URL: https://doi.org/10.1002/gcc.22726, doi:10.1002/gcc.22726. This article has 10 citations.
(martin‐guerrero2019non‐leukemicpediatricmixed pages 16-17): Idoia Martin‐Guerrero, Itziar Salaverria, Birgit Burkhardt, Catherine Chassagne‐Clement, Monika Szczepanowski, Susanne Bens, Wolfram Klapper, Martin Zimmermann, Edita Kabickova, Yves Bertrand, Alfred Reiter, Reiner Siebert, and Ilske Oschlies. Non‐leukemic pediatric mixed phenotype acute leukemia/lymphoma: genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma. Genes, Chromosomes and Cancer, 58(6):365-372, Jan 2019. URL: https://doi.org/10.1002/gcc.22726, doi:10.1002/gcc.22726. This article has 10 citations.
(mumme2023singlecellrnasequencing pages 4-5): Hope L. Mumme, Sunil S. Raikar, Swati S. Bhasin, Beena E. Thomas, Taylor Lawrence, Elizabeth P. Weinzierl, Yakun Pang, Deborah DeRyckere, Chuck Gawad, Daniel S. Wechsler, Christopher C. Porter, Sharon M. Castellino, Douglas K. Graham, and Manoj Bhasin. Single-cell rna sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia. Genome Medicine, Oct 2023. URL: https://doi.org/10.1186/s13073-023-01241-z, doi:10.1186/s13073-023-01241-z. This article has 20 citations and is from a highest quality peer-reviewed journal.
(NCT02135874 chunk 2): Clofarabine, Idarubicin, Cytarabine, Vincristine Sulfate, and Dexamethasone in Treating Patients With Newly Diagnosed or Relapsed Mixed Phenotype Acute Leukemia. M.D. Anderson Cancer Center. 2014. ClinicalTrials.gov Identifier: NCT02135874

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Mixed Phenotype Acute Leukemia: Disease Characteristics Research Report

Executive summary

1. Disease information

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2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

Recurrent somatic lesions

Epigenetics and functional consequence

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8. Temporal development

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