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Classifications

ICD-O Morphology

Harrison's Part

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Subtypes

10

Acute Megakaryoblastic Leukemia in Down Syndrome MONDO:0020526

The megakaryoblastic leukemia phenotype arising in young children with Down syndrome. Acquired GATA1s-generating mutations are highly recurrent. This is represented within the broader ML-DS clinical category, whose published treatment cohorts are not always stratified by megakaryoblastic morphology. TAM is a distinct neonatal precursor condition rather than overt AMKL.

Show evidence (2 references)

PMID:12172547 SUPPORT Human Clinical

"leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1"

This directly supports the DS-AMKL phenotype and its recurrent acquired GATA1 mutation.

PMID:35732831 SUPPORT Other

"Myeloid proliferations associated with Down syndrome, typically associated with somatic exon 2 or 3 GATA1 mutation, continue to encompass two clonal conditions that arise in children with constitutional trisomy 21: transient abnormal myelopoiesis (TAM), which is conﬁned to the ﬁrst 6 months of..."

WHO separates neonatal TAM from ML-DS while placing both in the trisomy-21/GATA1 disease spectrum.

Acute Megakaryoblastic Leukemia Without Down Syndrome MONDO:0018004

AMKL without constitutional Down syndrome. This age-spanning umbrella includes pediatric non-Down-syndrome AMKL and adult AMKL, which have different genomic architectures and treatment outcomes.

Pediatric Non-Down Syndrome AMKL
Adult AMKL

Show evidence (1 reference)

PMID:35732831 SUPPORT Other

"which arises within three clinical groups: children with Down syndrome, children without Down syndrome, and adults."

WHO distinguishes children without Down syndrome from adults while both remain within the broader non-Down-syndrome umbrella.

Pediatric Acute Megakaryoblastic Leukemia Without Down Syndrome

Pediatric AMKL without constitutional Down syndrome. It is composed of recurrent, usually mutually exclusive molecular subgroups with different outcomes. These are molecular subgroups among AML cases with megakaryoblastic differentiation and are not all formal WHO disease classes. No exact pediatric-umbrella ontology class is bound here.

RBM15::MRTFA-Rearranged AMKL
CBFA2T3::GLIS2-Positive AMKL
NUP98::KDM5A-Positive AMKL
KMT2A-Rearranged AMKL
HOX-Rearranged AMKL
GATA1-Mutant Non-Down Syndrome AMKL

Show evidence (1 reference)

PMID:28112737 SUPPORT Human Clinical

"We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes."

Genomic profiling establishes pediatric non-DS AMKL as a collection of distinct molecular subgroups.

Infant AMKL with t(1;22) RBM15::MRTFA MONDO:0018436

An infant-predominant non-DS AMKL subgroup defined by t(1;22)(p13;q13), which creates the RBM15::MRTFA fusion (historically RBM15-MKL1 or OTT-MAL).

Show evidence (1 reference)

PMID:11431691 SUPPORT Human Clinical

"Here we show this chromosomal rearrangement to result in the fusion of two novel genes, RNA-binding motif protein-15 (RBM15), an RNA recognition motif-encoding gene with homology to Drosophila spen, and Megakaryoblastic Leukemia-1 (MKL1)"

The original molecular report identifies the two partners created by t(1;22).

CBFA2T3::GLIS2-Positive AMKL

A high-risk pediatric non-DS AMKL subgroup with a cryptic chromosome 16 inversion. The same fusion also occurs in AML with other morphologies, so the broader CBFA2T3::GLIS2-positive AML ontology class is not used as an exact AMKL subtype binding here.

Show evidence (1 reference)

PMID:31719049 SUPPORT Human Clinical

"the presence of this fusion was highly associated with adverse outcome (P < 0.001) across all morphologic classifications."

The fusion is prognostically adverse but is not restricted to megakaryoblastic morphology.

NUP98::KDM5A-Positive AMKL NCIT:C132111

A recurrent pediatric non-DS molecular subgroup defined by the NUP98::KDM5A fusion. Cohort estimates trend toward adverse outcome, but small numbers preclude treating that effect as independently established. Depending on the classification framework, a fusion-defined AML category may take precedence while megakaryoblastic differentiation remains clinically relevant.

Show evidence (2 references)

PMID:31698461 SUPPORT Other

"Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A."

This identifies NUP98::KDM5A as the predominant NUP98 rearrangement in pediatric AMKL.

PMID:28112737 SUPPORT Human Clinical

"NUP98-KDM5A cases also demonstrated a trend towards poor outcomes, however due to small numbers this failed to reach statistical significance."

This supports an adverse trend while preserving the cohort's statistical uncertainty.

KMT2A-Rearranged AMKL

A mutually exclusive founding genomic subgroup among pediatric non-DS AML cases with megakaryoblastic differentiation. KMT2A-rearranged AML can be a genetically defined AML category rather than a formal AMKL child class. The subgroup is associated with a HOX transcriptional program and adverse outcome.

Show evidence (3 references)

PMID:27114462 SUPPORT Human Clinical

"NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive."

This supports KMT2A rearrangement as a mutually exclusive defining subgroup rather than a generic cooperating lesion.

PMID:28112737 SUPPORT Human Clinical

"Specifically, CBFA2T3-GLIS2 and KMT2Ar were found to have significantly inferior pEFS and pOS."

This directly supports the adverse outcome association in the genomic cohort.

PMID:23045605 SUPPORT Human Clinical

"One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes."

Patient expression data support the KMT2A/MLL-associated HOXA program.

HOX-Rearranged AMKL

A pediatric non-DS molecular subgroup among AML cases with megakaryoblastic differentiation, with diverse rearrangements involving HOX loci, a shared HOX expression program, and enrichment for activating MPL mutations.

Show evidence (2 references)

PMID:28112737 SUPPORT Human Clinical

"Collectively, fusions involving a HOX cluster gene (HOXr) occurred in 14% of patients within this cohort"

This defines and quantifies the HOX-rearranged subgroup in the reported pediatric cohort.

PMID:28112737 SUPPORT Human Clinical

"HOXr cases were found to be significantly enriched in activating MPL mutations"

This directly supports the subgroup's recurrent MPL association.

GATA1-Mutant Non-Down Syndrome AMKL

A distinct pediatric molecular subgroup without clinical Down syndrome or full constitutional trisomy 21, in which somatic GATA1 truncation usually co-occurs with acquired amplification of chromosome 21 material and produces a Down syndrome-like expression signature. Rare mosaic trisomy 21 must be specifically assessed rather than assumed absent from phenotype alone.

Show evidence (2 references)

PMID:28112737 SUPPORT Human Clinical

"Nine of ten GATA1 mutant cases had amplifications in the DSCR"

This directly corrects the older claim that GATA1 mutation is absent from non-DS AMKL.

PMID:28112737 SUPPORT Human Clinical

"One patient had non-hematopoietic tissue available for analysis and was found to be germline mosaic for trisomy 21"

This documents the mosaic-trisomy exception and the need for appropriate constitutional testing.

Acute Megakaryoblastic Leukemia in Adults MONDO:0971091

Adult AMKL is uncommon and biologically distinct from pediatric disease. Recurrent pediatric fusion subgroups are generally absent; adult cohorts instead show adverse cytogenetics and recurrent alterations in genes such as TET2, TP53, JAK2, PTPN11, and RUNX1.

Show evidence (2 references)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

A dedicated adult cohort establishes a genomic profile distinct from the recurrent pediatric fusions.

PMID:28112737 SUPPORT Human Clinical

"In contrast, in the adult cohort (n=24) which lacked recurrent fusion genes"

This direct pediatric-adult comparison supports the stated absence of recurrent pediatric fusion groups in that adult cohort.

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Mechanistic Hypotheses

3

Multistep Leukemogenesis in Down Syndrome

ml_ds_multistep_leukemogenesis CANONICAL Down Syndrome-Associated AMKL

Evidence balance 3 support

Trisomy 21 and a GATA1s-generating mutation establish the TAM clone; additional somatic lesions are implicated in progression to overt ML-DS.

Pathograph links

Trisomy 21 and GATA1 Truncation Generate GATA1s -> GATA1s-Driven Transient Abnormal Myelopoiesis DIRECT In a trisomy-21 hematopoietic background, GATA1s is sufficient to produce the preleukemic TAM state in experimental models.

Show evidence (3 references)

PMID:35203280 SUPPORT Other

"GATA1s, together with trisomy 21, is sufficient to develop a pre-leukemic condition called transient abnormal myelopoiesis (TAM)."

This is background synthesis in the model paper, not a result of the iPSC experiment itself.

PMID:21849481 SUPPORT Human Clinical

"Among all, AML subsequently occurred in 16% at a median of 441 days"

Prospective natural history shows that only a subset of TAM cases later develop leukemia.

PMID:35203280 SUPPORT In Vitro

"Hematopoietic differentiation of GATA1 STAG2 double-mutant iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein, leading to enhanced production of immature megakaryocytic population compared to GATA1 mutant alone."

This models one cooperating lesion that intensifies an immature megakaryocytic phenotype without proving overt leukemic conversion.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

pediatric_non_ds_genomic_subgroups CANONICAL Pediatric Non-Down Syndrome AMKL

Evidence balance 1 support

Pediatric non-DS AMKL comprises mutually exclusive genomic subgroups whose founding lesions define distinct transcriptional programs, cooperating alterations, and clinical risks within an immature megakaryocytic leukemic state.

Pathograph links

RBM15::MRTFA Fusion Deregulates RBPJ Transcription -> Immature Megakaryocytic Leukemic State INDIRECT KNOWN INTERMEDIATES Fusion-driven RBPJ dysregulation, together with engineered activating MPL signaling, produced an immature megakaryoblastic leukemia in the model.

CBFA2T3::GLIS2 Induces BMP Signaling and Progenitor Self-Renewal -> Immature Megakaryocytic Leukemic State INDIRECT KNOWN INTERMEDIATES Fusion-induced self-renewal and transformation can produce an immature leukemic state, although the cited experiment does not establish every component of megakaryocytic lineage specification.

NUP98::KDM5A Sustains Progenitor Capacity and Maturation Arrest -> Immature Megakaryocytic Leukemic State INDIRECT UNKNOWN INTERMEDIATES NUP98::KDM5A directly causes maturation arrest in engineered cells, while the path from that state to megakaryocytic leukemia remains model- and context-dependent.

KMT2A- and NUP98-Rearranged HOXA Program -> Immature Megakaryocytic Leukemic State UNKNOWN The fusion-associated HOXA program is present in these AMKL cohorts, but the expression association alone does not establish a causal route to the megakaryocytic leukemic phenotype.

HOX Rearrangement and MPL/JAK-STAT Cooperation -> Immature Megakaryocytic Leukemic State INDIRECT KNOWN INTERMEDIATES Activating MPL supplies a JAK-STAT-dependent growth advantage to the HOX-rearranged experimental system and may contribute to leukemic-cell persistence.

Non-DS GATA1 Mutation Cooperates with Chromosome 21 Gain -> Immature Megakaryocytic Leukemic State UNKNOWN GATA1 mutation and acquired chromosome-21 gain are associated with a DS-AMKL-like expression program, but the cohort does not resolve a causal path to the clinical blast phenotype.

Show evidence (1 reference)

PMID:28112737 SUPPORT Human Clinical

"These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes."

Large-scale sequencing supports a subgroup model with founding fusions and subgroup-specific cooperating lesions.

Distinct Adult AMKL Genomic Model

adult_amkl_distinct_genomic_model CANONICAL Adult AMKL

Evidence balance 1 support

Adult AMKL is not simply an age-shifted pediatric fusion leukemia; it is characterized by adverse cytogenetics, a different mutation spectrum, and marked treatment resistance.

Show evidence (1 reference)

PMID:28112737 SUPPORT Human Clinical

"In contrast, in the adult cohort (n=24) which lacked recurrent fusion genes, the most highly recurrent mutations were in TP53 (20.8%), cohesin genes (16.7%), splicing factor genes (16.7%), ASXL genes (16.7%) and DNMT3A (12.5%)"

Direct pediatric-adult comparison supports a separate adult genomic model.

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Discussions and Knowledge Gaps

5

Which molecular-risk groups of pediatric non-DS AMKL derive a net survival benefit from allogeneic HCT in first complete remission rather than chemotherapy alone?

CONTROVERSY OPEN controversy_amkl_hct_cr1_benefit

Attached to

treatments#Allogeneic Hematopoietic Cell Transplantation for Selected Pediatric Non-DS AMKL has_subtypes#CBFA2T3::GLIS2-Positive AMKL has_subtypes#NUP98::KDM5A-Positive AMKL

Retrospective series disagree and are vulnerable to selection, response, molecular-composition, and treatment-era effects. The entry therefore encodes HCT as risk-adapted and uncertain rather than uniformly beneficial.

Show evidence (3 references)

PMID:25913479 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit"

One large pediatric cohort found no significant CR1 survival advantage.

PMID:36786154 SUPPORT Human Clinical

"Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1."

Registry investigators explicitly leave CR1 indication unresolved.

PMID:41228304 SUPPORT Human Clinical

"Treatment with allo-HSCT did not improve outcomes due to the high CIR, even after HSCT in CR1."

A recent single-center comparison reinforces the uncertainty.

What induction formulation and dose intensity preserves ML-DS event-free survival while minimizing treatment-related toxicity?

KNOWLEDGE GAP OPEN gap_ml_ds_dose_intensity

Attached to

treatments#Reduced-Intensity Cytarabine-Based Chemotherapy for ML-DS has_subtypes#Down Syndrome-Associated AMKL

ML-DS 2006 preserved outcome after selected reductions, whereas replacing induction with CPX-351 in ML-DS 2018 reduced EFS despite favorable toxicity.

Show evidence (2 references)

PMID:28400376 SUPPORT Human Clinical

"Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome."

Selected reductions preserved outcomes in ML-DS 2006.

PMID:41118594 SUPPORT Human Clinical

"replacing intensity-reduced induction therapy with CPX-351 in ML-DS led to a significantly lower EFS, highlighting the need for dose optimization to balance the efficacy and toxicity"

A different substitution strategy failed to preserve EFS.

How much of human RBM15::MRTFA AMKL is faithfully modeled by the Ott-Mal donor-marrow/MPLW515L transduction-transplant system used to produce short-latency leukemia?

HUMAN MODEL MISMATCH OPEN interpretation_rbm15_mrtfa_mpl_model

Attached to

pathophysiology#RBM15::MRTFA Fusion Deregulates RBPJ Transcription animal_models#Ott-Mal knock-in donor marrow retrovirally transduced ex vivo with MPLW515L and transplanted into lethally irradiated WT C57BL/6 recipients

The model demonstrates functional cooperation and reproduces many human features, but it may overrepresent MPL-dependent biology.

Proposed experiments

RBM15::MRTFA dependence on forced MPL signaling across matched human and mouse models

exp_amkl_rbm15_mrtfa_mpl_dependency

Profile MPL-pathway lesions and signaling in human RBM15::MRTFA-positive AMKL, then compare Ott-Mal knock-in donor marrow transplanted after matched no-vector, MPL-WT, and MPLW515L transduction. Measure leukemia latency, lineage state, fibrosis, and transcriptional similarity to the human tumors.

Decision criterion

Determine whether fusion-positive human tumors share the MPL-dependent state required for short-latency leukemia in the mouse transplant model.

Show evidence (1 reference)

PMID:19287095 SUPPORT Model Organism

"cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL"

This is both the model's mechanistic strength and the reason to qualify extrapolation to every human fusion-positive case.

Which recurrent adult AMKL genomic lesions directly specify megakaryoblastic differentiation and which primarily mark adverse-risk clonal myeloid disease?

KNOWLEDGE GAP OPEN gap_adult_amkl_causal_biology

Attached to

pathophysiology#Adult Adverse Genomic Landscape and Therapy Resistance has_subtypes#Adult AMKL

Adult cohorts define recurrent mutations and dismal outcomes, but do not resolve a causal differentiation program comparable with pediatric fusion subgroups.

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

The cohort defines the association set but not lesion-specific differentiation mechanisms.

Which preclinical AMKL targets can produce safe and durable clinical benefit across or within molecular subgroups?

KNOWLEDGE GAP OPEN gap_preclinical_target_translation

Attached to

experimental_models#NUP98-KDM5A Cord-Blood HSPC Model experimental_models#CBFA2T3-GLIS2 Cord-Blood HSPC Endothelial Coculture

Aurora A inhibition, JAK inhibition, CD56-directed therapy, and FOLR1 CAR T cells have promising model evidence, but none is encoded as established AMKL treatment. On-target FOLR1 expression in normal kidney and lung raises a specific safety concern.

Show evidence (2 references)

PMID:36136600 SUPPORT Other

"FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy."

This directly identifies the translational safety barrier for the preclinical FOLR1 strategy.

PMID:31698461 SUPPORT In Vitro

"Both synthetic models and patient-derived xenografts of NUP98-rearranged AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically approved JAK2 inhibitor."

This is preclinical vulnerability evidence, not an AMKL clinical efficacy result.

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Pathophysiology

13

Trisomy 21 and GATA1 Truncation Generate GATA1s

In the usual Down syndrome-associated sequence, an acquired GATA1 mutation introduces a premature stop in the N-terminal activation domain. Full-length GATA1 is lost while a shorter downstream-initiated GATA1s protein is retained. The trisomy-21 fetal hematopoietic context and GATA1s cooperate to establish the precursor clone.

Multistep Leukemogenesis in Down Syndrome

megakaryocyte progenitor cell CL:0000553

GATA1 hgnc:4170

Experimental models

Trisomy-21 GATA1/STAG2 Double-Mutant iPSC Model IPSC DERIVED MODEL Recapitulates GATA1s production in trisomy-21 hematopoietic progenitors.

Downstream

GATA1s-Driven Transient Abnormal Myelopoiesis In a trisomy-21 hematopoietic background, GATA1s is sufficient to produce the preleukemic TAM state in experimental models.

Show evidence (1 reference)

PMID:12172547 SUPPORT Human Clinical

"These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream."

This directly establishes the protein-level consequence of the GATA1-truncating mutations.

GATA1s-Driven Transient Abnormal Myelopoiesis

TAM is a neonatal clonal myeloid proliferation restricted to infants with trisomy 21 and GATA1s. It often resolves spontaneously and is not itself AMKL, but it is the recognized precursor from which a subset of ML-DS cases later emerge.

GATA1 hgnc:4170

Show evidence (2 references)

PMID:14636651 SUPPORT Human Clinical

"We detected GATA1 mutations in TMD blasts from every infant examined."

This establishes GATA1 mutation as an early event already present in the transient precursor clone.

PMID:21849481 SUPPORT Human Clinical

"Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively."

Prospective observation documents the characteristic spontaneous resolution of TAM.

STAG2 Loss Enhances Immature Megakaryopoiesis in a Trisomy-21/GATA1s iPSC Model

In gene-targeted trisomy-21/GATA1-mutant iPSCs, STAG2 loss enhanced production of an immature megakaryocytic population relative to GATA1 mutation alone. This is one progression model; it does not establish that STAG2 loss alone converts TAM into overt ML-DS or AMKL in vivo.

megakaryocyte progenitor cell CL:0000553

STAG2 hgnc:11355

Experimental models

Trisomy-21 GATA1/STAG2 Double-Mutant iPSC Model IPSC DERIVED MODEL Models the incremental effect of engineered STAG2 loss beyond GATA1 mutation alone.

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"Hematopoietic differentiation of GATA1 STAG2 double-mutant iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein, leading to enhanced production of immature megakaryocytic population compared to GATA1 mutant alone."

Sequential editing shows that STAG2 loss intensifies the immature megakaryocytic state beyond GATA1s alone.

RBM15::MRTFA Fusion Deregulates RBPJ Transcription

The t(1;22) fusion joins RBM15 to MRTFA (formerly MKL1). In a knock-in mouse model the fusion deregulates RBPJ-mediated canonical Notch transcription and abnormal fetal megakaryopoiesis; cooperation with activating MPL is required for short-latency model disease.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

RBM15 hgnc:14959 MRTFA hgnc:14334

Downstream

Immature Megakaryocytic Leukemic State Fusion-driven RBPJ dysregulation, together with engineered activating MPL signaling, produced an immature megakaryoblastic leukemia in the model.

Show evidence (1 reference)

PMID:19287095 SUPPORT Model Organism

"OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal megakaryopoiesis."

The knock-in model directly supports RBPJ/Notch transcriptional dysregulation.

CBFA2T3::GLIS2 Induces BMP Signaling and Progenitor Self-Renewal

The cryptic inv(16)(p13.3q24.3) CBFA2T3::GLIS2 fusion increases BMP signaling and self-renewal in experimental hematopoietic progenitors. Human transcriptomic studies also associate the fusion with Hippo, TGF-beta, and Hedgehog pathway dysregulation, but those associations are not modeled here as individually proven causal edges.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

CBFA2T3 hgnc:1537 GLIS2 hgnc:29450

BMP signaling pathway GO:0030509 ↑ INCREASED stem cell population maintenance GO:0019827 ↑ INCREASED

Downstream

Immature Megakaryocytic Leukemic State Fusion-induced self-renewal and transformation can produce an immature leukemic state, although the cited experiment does not establish every component of megakaryocytic lineage specification.

Show evidence (1 reference)

PMID:23153540 SUPPORT Model Organism

"Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors."

Cross-species functional experiments directly support BMP activation and increased progenitor self-renewal.

NUP98::KDM5A Sustains Progenitor Capacity and Maturation Arrest

NUP98::KDM5A is a potent driver of maturation arrest and long-term proliferative/progenitor capacity in engineered human hematopoietic cells. Model systems also show JAK-STAT upregulation and drug sensitivity, but these preclinical dependencies are not established clinical treatments.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

NUP98 hgnc:8068 KDM5A hgnc:9886

Experimental models

NUP98-KDM5A Cord-Blood HSPC Model PRIMARY CELL CULTURE Models the fusion-driven leukemic state.

Downstream

Immature Megakaryocytic Leukemic State NUP98::KDM5A directly causes maturation arrest in engineered cells, while the path from that state to megakaryocytic leukemia remains model- and context-dependent.

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions."

The engineered human-cell system directly supports maturation arrest and persistent progenitor capacity.

KMT2A- and NUP98-Rearranged HOXA Program

KMT2A (historically MLL) and NUP98 fusions define distinct pediatric subgroups but converge at the level of HOXA-cluster upregulation. This node models the shared transcriptional program without treating KMT2A as a cooperating lesion of another fusion subgroup.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

KMT2A hgnc:7132 NUP98 hgnc:8068

Downstream

Immature Megakaryocytic Leukemic State The fusion-associated HOXA program is present in these AMKL cohorts, but the expression association alone does not establish a causal route to the megakaryocytic leukemic phenotype.

Show evidence (1 reference)

PMID:23045605 SUPPORT Human Clinical

"One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes."

Patient genomic and expression data support a shared HOXA program in KMT2A/MLL- and NUP98-rearranged disease.

HOX Rearrangement and MPL/JAK-STAT Cooperation

HOX-rearranged pediatric AMKL is enriched for activating MPL mutations. Experimental co-expression of a HOX rearrangement and mutant MPL produces a cytokine-independent growth advantage with phosphorylated JAK2 and STAT5, supporting subgroup-specific signaling cooperation.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

MPL hgnc:7217

Downstream

Immature Megakaryocytic Leukemic State Activating MPL supplies a JAK-STAT-dependent growth advantage to the HOX-rearranged experimental system and may contribute to leukemic-cell persistence.

Show evidence (2 references)

PMID:28112737 SUPPORT Human Clinical

"HOXr cases were found to be significantly enriched in activating MPL mutations"

Human tumors establish enrichment of activating MPL mutations in this subgroup.

PMID:28112737 SUPPORT In Vitro

"Activated JAK-STAT signaling as determined by phosphorylated JAK2 and STAT5 was found in HOXr cells containing a MPL mutation"

Cytokine-withdrawal experiments provide a functional signaling readout for HOXr/MPL cooperation.

Non-DS GATA1 Mutation Cooperates with Chromosome 21 Gain

A non-DS pediatric subgroup carries somatic GATA1 truncation without constitutional trisomy 21. Most reported cases had acquired amplification of the Down syndrome critical region and a transcriptional profile closely resembling DS-AMKL.

Fusion-Defined Pediatric Non-DS AMKL Subgroups

GATA1 hgnc:4170

Downstream

Immature Megakaryocytic Leukemic State GATA1 mutation and acquired chromosome-21 gain are associated with a DS-AMKL-like expression program, but the cohort does not resolve a causal path to the clinical blast phenotype.

Show evidence (1 reference)

PMID:28112737 SUPPORT Human Clinical

"Nine of ten GATA1 mutant cases had amplifications in the DSCR"

This establishes recurrent acquired chromosome-21 amplification in GATA1-mutant non-DS disease.

Adult Adverse Genomic Landscape and Therapy Resistance

Adult AMKL cohorts show adverse cytogenetics, frequent chromosome 1q aberrations, and recurrent mutations unlike the pediatric fusion spectrum. These observations are clinically associated with low remission rates and short survival; which lesions are causal for megakaryoblastic differentiation remains unresolved.

TET2 hgnc:25941 TP53 hgnc:11998 JAK2 hgnc:6192 PTPN11 hgnc:9644 RUNX1 hgnc:10471

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks"

The adult cohort documents profound treatment resistance and poor outcome.

Immature Megakaryocytic Leukemic State

AMKL is defined by an acute leukemic blast population with megakaryocytic differentiation. The cells can retain multilineage potential; available human evidence does not establish one universal maturation block or require assignment to a fully committed megakaryocyte-erythroid progenitor.

megakaryocyte progenitor cell CL:0000553

bone marrow UBERON:0002371

Experimental models

Trisomy-21 GATA1/STAG2 Double-Mutant iPSC Model IPSC DERIVED MODEL Measures enhanced production of an immature megakaryocytic population in vitro.

NUP98-KDM5A Cord-Blood HSPC Model PRIMARY CELL CULTURE Recapitulates maturation arrest and sustained progenitor capacity.

CBFA2T3-GLIS2 Cord-Blood HSPC Endothelial Coculture CO CULTURE Recapitulates fusion-positive AML morphology and immunophenotype.

Downstream

PDGF-Associated Marrow Fibrosis PDGF-BB positivity in megakaryoblasts is associated with marrow fibrosis; direction and causality are unresolved.

Extramedullary Leukemic Infiltration Megakaryoblastic tissue infiltration co-occurs with the leukemic blast state in infant t(1;22) disease; the observational series does not establish a direct causal transition.

Anemia Anemia accompanies the leukemic marrow state, but the cached clinical evidence does not resolve the relative effects of marrow replacement, fibrosis, inflammation, and treatment.

Thrombocytopenia Low platelet counts are common in reported pediatric cohorts, but AMKL can also present with normal counts and the mechanism is not captured by one universal causal route.

Show evidence (2 references)

PMID:8069184 SUPPORT Human Clinical

"The target cells of AMKL and TAM are immature cells close to stem cells which are capable of differentiating into lineage cells such as megakaryocytes, erythrocytes and myeloid cells."

This supports an immature, multilineage-capable cell state while avoiding an unsupported universal cell-of-origin claim.

PMID:35732831 SUPPORT Other

"Blasts express at least one or more of the platelet glycoproteins: CD41 (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)"

WHO anchors the clinical disease state in megakaryocytic-lineage marker expression.

PDGF-Associated Marrow Fibrosis

AMKL marrow commonly shows reticulin fibrosis. In a clinicopathologic series, PDGF-BB staining in megakaryoblasts and some fibroblasts tracked with the presence of fibrosis, supporting a growth-factor-associated stromal response while leaving additional mediators unresolved.

megakaryocyte progenitor cell CL:0000553

bone marrow UBERON:0002371

Downstream

Myelofibrosis PDGF positivity and myelofibrosis co-occurred in the examined cases; this edge records the unresolved association rather than a proven direct effect.

Show evidence (1 reference)

PMID:23530558 SUPPORT Human Clinical

"Nine of the 11 cases examined immunohistochemically were positive for platelet-derived growth factor (PDGF)(-BB), especially megakaryoblasts and a few fibroblasts."

This localizes PDGF-BB immunoreactivity to megakaryoblasts and some fibroblasts in the reported cases.

Extramedullary Leukemic Infiltration

Leukemic megakaryoblasts may form cohesive infiltrates in liver, lymph node, and other tissues. This is particularly well documented in infant t(1;22) AMKL and can resemble a nonhematopoietic small-round-cell tumor.

Downstream

Hepatosplenomegaly Tissue infiltration and liver/spleen enlargement co-occurred in the six reported infants; direction and causality were not tested.

Show evidence (1 reference)

PMID:1510033 SUPPORT Human Clinical

"Biopsy specimens of the liver and lymph node were suggestive of a nonhematopoietic malignant condition because of the cohesiveness of the tumor cells, stromal fibrosis, and the prominent sinusoidal and vascular pattern of infiltration."

This describes the characteristic tissue infiltration pattern in the infant t(1;22) cohort.

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Histopathology

2

Megakaryoblast Infiltration

Blood or marrow contains abnormal blasts with megakaryocytic differentiation. Lineage confirmation relies on platelet glycoproteins such as CD41, CD61, or CD42b. No current ontology binding is supplied because NCIT:C155995 denotes generic myeloblasts rather than megakaryoblasts.

Show evidence (1 reference)

PMID:35732831 SUPPORT Other

"Blasts express at least one or more of the platelet glycoproteins: CD41 (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)"

WHO defines the lineage by platelet-glycoprotein expression on blasts.

Marrow Reticulin Fibrosis FREQUENT

Reticulin fibrosis is variable. The FREQUENT band reflects a 75% rate in one prospective pediatric series and should not be read as a universal age- or subtype-independent estimate.

Show evidence (1 reference)

PMID:12749007 SUPPORT Human Clinical

"Bone marrow (BM) fibrosis was a constant features in our patients; 75% of the patients studied showed this complication at the time of diagnosis."

This supplies a disease-specific pediatric cohort estimate for fibrosis.

⬡

Pathograph

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

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Phenotypes

4

Blood 2

Anemia HP:0001903

Show evidence (2 references)

PMID:23530558 SUPPORT Human Clinical

"All cases had anaemia, but leukocyte and platelet counts varied."

All 18 cases in this clinicopathologic series had anemia.

PMID:1510033 SUPPORT Human Clinical

"All the patients had hepatosplenomegaly and anemia (6 to 8.3 g/dL)"

All six infants with t(1;22) AMKL had severe anemia.

Thrombocytopenia HP:0001873

Show evidence (2 references)

PMID:33812402 SUPPORT Human Clinical

"the median hemoglobin was 67 g/L and median platelet was 16×109/L."

The reported median platelet count was markedly low in this 19-child non-DS cohort.

PMID:1510033 SUPPORT Human Clinical

"four patients had thrombocytopenia (9,000 to 63,000/mm3)."

Four of six infants with t(1;22) AMKL were thrombocytopenic.

Cardiovascular 1

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:1510033 SUPPORT Human Clinical

"All the patients had hepatosplenomegaly and anemia"

All six infants in this molecularly defined series had hepatosplenomegaly; no categorical prevalence is extrapolated from that small cohort.

Other 1

Myelofibrosis FREQUENT HP:0011974

Show evidence (1 reference)

PMID:12749007 SUPPORT Human Clinical

"75% of the patients studied showed this complication at the time of diagnosis."

The frequency band is tied to this prospective pediatric cohort rather than generalized to every subtype.

🧬

Genetic Associations

16

GATA1 Somatic Truncating Mutations (GATA1s-generating truncation is a somatic driver in TAM/ML-DS and in a distinct pediatric non-DS AMKL subgroup.)

Gene: GATA1 hgnc:4170 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (4 references)

PMID:12172547 SUPPORT Human Clinical

"leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1"

This establishes the recurrent somatic driver in DS-AMKL.

PMID:28112737 SUPPORT Human Clinical

"GATA1 mutant calls were absent from these remission samples"

Absence from matched remission samples supports a somatic origin in the evaluated pediatric non-DS cases.

PMID:35732831 SUPPORT Other

"Myeloid proliferations associated with Down syndrome, typically associated with somatic exon 2 or 3 GATA1 mutation ... transient abnormal myelopoiesis (TAM) ... and myeloid leukaemia of Down syndrome (ML-DS)."

WHO links somatic GATA1 mutation to both TAM and ML-DS.

+ 1 more reference

Germline GATA1s-Generating Susceptibility Variants (Rare germline GATA1s-generating variants predispose to early-childhood AMKL after acquired trisomy 21 or tetrasomy 21.)

Gene: GATA1 hgnc:4170 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:34758059 SUPPORT Human Clinical

"We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21."

Two families establish a rare germline susceptibility state followed by acquired chromosome-21 gain in evaluable leukemias.

RBM15 (Somatic driver fusion partner in t(1;22) AMKL)

Gene: RBM15 hgnc:14959 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:11431691 SUPPORT Human Clinical

"we show this chromosomal rearrangement to result in the fusion of two novel genes, RNA-binding motif protein-15 (RBM15) ... and Megakaryoblastic Leukemia-1 (MKL1)"

The original report directly identifies RBM15 as one fusion partner.

MRTFA (Somatic driver fusion partner, historically named MKL1 or MAL)

Gene: MRTFA hgnc:14334 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:11431691 SUPPORT Human Clinical

"we show this chromosomal rearrangement to result in the fusion of two novel genes, RNA-binding motif protein-15 (RBM15) ... and Megakaryoblastic Leukemia-1 (MKL1)"

The original report directly identifies MKL1, now MRTFA, as the second fusion partner.

CBFA2T3 (Somatic driver fusion partner in cryptic inv(16))

Gene: CBFA2T3 hgnc:1537 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23153540 SUPPORT Human Clinical

"Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein."

This identifies the cryptic rearrangement and its fusion product.

GLIS2 (Somatic driver fusion partner in cryptic inv(16))

Gene: GLIS2 hgnc:29450 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23153540 SUPPORT Model Organism

"These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis."

Functional models support the fusion's driver role.

NUP98 (Somatic driver fusion partner, most commonly with KDM5A in AMKL)

Gene: NUP98 hgnc:8068 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:31698461 SUPPORT Human Clinical

"Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A."

This supports NUP98 rearrangement as a recurrent driver class.

KDM5A (Somatic driver fusion partner of NUP98)

Gene: KDM5A hgnc:9886 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest"

Engineered human-cell models support the fusion's driver effect without assigning unsupported retained JmjC demethylase activity.

KMT2A (Mutually exclusive somatic driver rearrangement in pediatric non-DS AMKL)

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

Show evidence (1 reference)

PMID:27114462 SUPPORT Human Clinical

"NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive."

This supports KMT2A rearrangement as a recurrent, mutually exclusive molecular subgroup.

MPL (Activating cooperating alteration enriched in HOX-rearranged AMKL)

Gene: MPL hgnc:7217 relationship_type: COOPERATING variant_origin: SOMATIC

Show evidence (2 references)

PMID:28112737 SUPPORT Human Clinical

"HOXr cases were found to be significantly enriched in activating MPL mutations"

This identifies the subgroup-specific cooperating alteration.

PMID:28112737 SUPPORT In Vitro

"When cells were removed from cytokine containing media, however, a growth advantage was identified in cells containing both a HOXr and a MPL mutation."

A colony-assay growth advantage provides functional, but model-limited, support for HOXr/MPL cooperation.

STAG2 (Cooperating cohesin alteration recurrent in DS-ML but not TAM; functional cooperation is supported in a trisomy-21/GATA1s iPSC model.)

Gene: STAG2 hgnc:11355 relationship_type: COOPERATING variant_origin: SOMATIC

Show evidence (2 references)

PMID:35203280 SUPPORT Other

"STAG2, a member of the cohesin complex recurrently mutated in DS-ML but not in TAM."

This supports association with the DS-ML state, not direct longitudinal acquisition during human progression.

PMID:35203280 SUPPORT In Vitro

"Hematopoietic differentiation of GATA1 STAG2 double-mutant iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein, leading to enhanced production of immature megakaryocytic population compared to GATA1 mutant alone."

The engineered iPSC comparison provides functional cooperation evidence without proving longitudinal acquisition in human disease.

TET2 (Recurrent adult AMKL genomic biomarker)

Gene: TET2 hgnc:25941 relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

This reports recurrent adult-cohort mutations without proving a gene-specific causal route to megakaryoblastic differentiation.

TP53 (Recurrent adult AMKL genomic biomarker)

Gene: TP53 hgnc:11998 relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

This reports recurrent adult-cohort mutations without proving a gene-specific causal route to megakaryoblastic differentiation.

JAK2 (Recurrent adult AMKL genomic biomarker)

Gene: JAK2 hgnc:6192 relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

This reports recurrent adult-cohort mutations without proving a gene-specific causal route to megakaryoblastic differentiation.

PTPN11 (Recurrent adult AMKL genomic biomarker)

Gene: PTPN11 hgnc:9644 relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

This reports recurrent adult-cohort mutations without proving a gene-specific causal route to megakaryoblastic differentiation.

RUNX1 (Recurrent adult AMKL genomic biomarker)

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

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%)."

This reports recurrent adult-cohort mutations without proving a gene-specific causal route to megakaryoblastic differentiation.

💊

Medical Actions

6

Reduced-Intensity Cytarabine-Based Chemotherapy for ML-DS

Category: Therapeutic Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Agent: cytarabine CHEBI:28680 etoposide CHEBI:4911

Children with ML-DS are treated with reduced-intensity AML regimens tailored to their high cytotoxic-drug susceptibility. In ML-DS 2006, reducing cumulative etoposide, reducing intrathecal prophylaxis, and omitting maintenance preserved excellent survival relative to the historical reduced-intensity control. This evidence supports a specific tested regimen, not arbitrary further deintensification, and applies to the ML-DS trial population rather than a morphology-stratified DS-AMKL subset.

Mechanism Target:

INHIBITS Immature Megakaryocytic Leukemic State — Cytotoxic therapy reduces leukemic cell burden; it does not reverse trisomy 21 or the GATA1 mutation.

Show evidence (1 reference)

PMID:28400376 SUPPORT Human Clinical

"Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ"

Clinical outcomes indirectly support control of leukemic burden; this does not establish reversal of the underlying differentiation program.

Show evidence (4 references)

PMID:28400376 SUPPORT Human Clinical

"Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility."

This directly supports tailoring intensity to the heightened cytotoxic drug susceptibility of children with ML-DS.

PMID:41118594 SUPPORT Human Clinical

"Intensity-reduced induction and reinduction therapy with cytarabine and idarubicin with or without etoposide was replaced with CPX-351"

ML-DS 2018 identifies the intensity-reduced predecessor backbone as cytarabine-based; it does not define the complete ML-DS 2006 regimen.

PMID:28400376 SUPPORT Human Clinical

"treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy."

This states the actual deintensification tested in ML-DS 2006.

+ 1 more reference

Intensive Pediatric AML Chemotherapy for Non-DS AMKL

Category: Therapeutic Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Pediatric non-DS AMKL is treated with intensive multi-agent AML therapy. Survival improved substantially between AML-BFM 98 and AML-BFM 04, but molecular subgroup and early response remain important risk variables.

Mechanism Target:

INHIBITS Immature Megakaryocytic Leukemic State — Intensive AML chemotherapy reduces leukemic cell burden; this is not a fusion-specific targeted effect or evidence of restored maturation.

Show evidence (1 reference)

PMID:25913479 SUPPORT Human Clinical

"we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041)."

Improved survival indirectly supports disease-burden control but does not establish a fusion-specific or differentiation-restoring mechanism.

Show evidence (4 references)

PMID:25913479 SUPPORT Human Clinical

"we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041)."

The prospective multicenter studies document improved survival in the later intensive-treatment era.

PMID:25913479 SUPPORT Human Clinical

"Nevertheless, with intensive therapy regimens, a steep increase in the survival rates was achieved."

This supports intensive AML therapy as the pediatric non-DS treatment backbone.

PMID:25913479 SUPPORT Human Clinical

"multivariate analysis showed that treatment response (bone marrow morphology on day 15 and 28) was the only independent prognostic marker"

This directly supports early morphologic response as a risk variable in the AML-BFM cohorts.

+ 1 more reference

Allogeneic Hematopoietic Cell Transplantation for Selected Pediatric Non-DS AMKL

Category: Therapeutic Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Allogeneic HCT may be considered for selected high-risk or poorly responding non-DS AMKL, but it is not a uniformly established CR1 standard. Comparative cohorts have not established a net CR1 survival benefit, while registry data among transplanted patients show better outcomes in CR1 than later or outside remission.

Mechanism Target:

INHIBITS Immature Megakaryocytic Leukemic State — Conditioning and graft-mediated antileukemic effects aim to eradicate the leukemic clone and restore donor hematopoiesis.

Show evidence (1 reference)

PMID:36786154 SUPPORT Human Clinical

"The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%)"

Outcomes by remission state indirectly support antileukemic disease control, without identifying a specific differentiation mechanism.

Show evidence (5 references)

PMID:25913479 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit"

This argues against encoding transplant as universally beneficial in CR1.

PMID:36786154 SUPPORT Human Clinical

"The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%)"

Among transplanted patients, remission state strongly affected outcome; the registry lacks a chemotherapy-only comparator.

PMID:41228304 SUPPORT Human Clinical

"Treatment with allo-HSCT did not improve outcomes due to the high CIR, even after HSCT in CR1."

A recent small cohort reinforces uncertainty about a CR1 survival benefit.

+ 2 more references

Intensive Chemotherapy for Fit Adults

Category: Therapeutic Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Fit adults may receive intensive AML chemotherapy, but dedicated AMKL data show low complete-remission rates and very short survival. This is a treatment option with limited effectiveness rather than a favorable evidence-based expectation.

Mechanism Target:

INHIBITS Immature Megakaryocytic Leukemic State — Intensive chemotherapy aims to reduce adult AMKL leukemic-cell burden.

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks"

The remission rate indirectly supports blast-burden reduction while the poor survival documents limited effectiveness.

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks"

This supports use of intensive therapy in the cohort while documenting its limited effectiveness.

Allogeneic Hematopoietic Cell Transplantation for Eligible Adults

Category: Therapeutic Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Adult cohort data describe allogeneic HSCT as the only potentially curative option, but selection bias is unavoidable and post-transplant relapse remains high.

Mechanism Target:

INHIBITS Immature Megakaryocytic Leukemic State — Transplant conditioning and graft-mediated effects aim to eliminate the resistant adult AMKL clone.

Show evidence (1 reference)

PMID:37455345 SUPPORT Human Clinical

"Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%)."

These outcomes indirectly support antileukemic disease control while documenting substantial post-transplant relapse.

Show evidence (2 references)

PMID:37455345 SUPPORT Human Clinical

"So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup."

This is the adult cohort authors' interpretation and is retained with partial support because the observational design cannot prove uniqueness.

PMID:37455345 SUPPORT Human Clinical

"Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%)."

This supports potential benefit while explicitly documenting high relapse.

GATA1 Measurable Residual Disease Monitoring in ML-DS

Category: Monitoring

Error-corrected next-generation sequencing of the leukemia-associated GATA1 mutation can monitor molecular residual disease in ML-DS. In ML-DS 2018, positivity was associated with increased relapse risk; this evidence does not establish generic flow-cytometric or fusion-based MRD monitoring for all AMKL subtypes.

Show evidence (1 reference)

PMID:41118594 SUPPORT Human Clinical

"Positive MRD by error-corrected GATA1 next-generation sequencing, the presence of trisomy 8 or a complex karyotype were associated with an increased risk for relapse."

This supports error-corrected GATA1 molecular MRD as a relapse-risk monitoring tool in the ML-DS 2018 population.

🔬

Diagnosis

4

Bone Marrow Morphology and Blast Assessment

Marrow aspirate and trephine biopsy establish the acute blast process and evaluate morphology. For morphology-defined AMKL lacking an AML-defining genetic alteration, the shared WHO AML threshold is at least 20% blasts in marrow and/or blood, with exclusion of other defined AML and mixed-phenotype entities.

biopsy of bone marrow NCIT:C15193

Results: An acute blast process with megakaryoblastic morphology supports AMKL once megakaryocytic lineage is confirmed and exclusion criteria are met.

Show evidence (1 reference)

PMID:35732831 SUPPORT Other

"Shared diagnostic criteria include: - ≥20% blasts in bone marrow and/or blood (except for acute erythroid leukaemia)."

WHO provides the shared blast criterion for morphology-defined AMKL.

Flow-Cytometric Confirmation of Megakaryocytic Differentiation

Lineage attribution can use flow cytometry and/or immunohistochemistry. With flow cytometry, demonstrate at least one platelet glycoprotein on blasts: CD41, CD61, or CD42b. A CD42a.CD61-positive/CD13-negative EuroFlow pattern is highly specific but only moderately sensitive and cannot be used as the sole rule.

flow cytometry procedure NCIT:C16585

Results: Platelet-glycoprotein expression confirms megakaryocytic differentiation in the appropriate acute leukemia context.

Show evidence (3 references)

PMID:35732831 SUPPORT Other

"Lineage attribution rests on ... ﬂow cytometry and/or immunohistochemistry."

WHO permits lineage attribution by flow cytometry and/or immunohistochemistry rather than requiring flow alone.

PMID:35732831 SUPPORT Other

"Blasts express at least one or more of the platelet glycoproteins: CD41 (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)"

WHO defines the lineage-confirming markers.

PMID:35326734 SUPPORT Human Clinical

"Combining CD42a.CD61 (positive) and CD13 (negative) resulted in a sensitivity of 71% and a specificity of 99%."

This quantifies a highly specific supportive flow pattern and its sensitivity limitation.

Cytogenetic Analysis

Tumor karyotyping and targeted FISH detect chromosome-21 abnormalities, t(1;22), KMT2A rearrangements, monosomy 7, and other risk lesions, but tumor testing alone cannot distinguish constitutional from acquired trisomy 21. Matched remission or nonhematopoietic tissue is needed to resolve that distinction, especially when mosaicism is possible. Cryptic CBFA2T3::GLIS2 and NUP98::KDM5A lesions require targeted FISH, RT-PCR, or sequencing rather than conventional karyotyping alone.

cytogenetic analysis NCIT:C18280

Results: Recurrent cytogenetic and fusion findings assign subtype and inform pediatric risk stratification.

Show evidence (3 references)

PMID:27114462 SUPPORT Human Clinical

"CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%."

This supports testing for recurrent molecular/cytogenetic risk groups.

PMID:28112737 SUPPORT Human Clinical

"CBFA2T3-GLIS2 and NUP98-KDM5A, are missed by conventional karyotyping and therefore require split-signal FISH or RT-PCR for detection."

This directly supports targeted testing for the two cryptic fusions.

PMID:28112737 SUPPORT Human Clinical

"One patient had non-hematopoietic tissue available for analysis and was found to be germline mosaic for trisomy 21"

This illustrates why tumor cytogenetics alone cannot exclude constitutional mosaic trisomy 21 and why matched nonhematopoietic tissue may be required.

Molecular Testing for GATA1 and Recurrent Fusions

In pediatric non-DS AMKL, the cohort-based core recommendation includes GATA1, CBFA2T3::GLIS2, KMT2A rearrangements, and NUP98::KDM5A. Broader RNA-based fusion profiling can detect additional RBM15::MRTFA and diverse HOX-rearranged subgroups. Molecular assignment supports risk stratification because major pediatric subgroups differ in outcome and some lesions are cryptic.

molecular genetic testing NCIT:C19770

Results: Molecular findings classify recurrent non-DS genomic subgroups and, when interpreted with constitutional-versus-acquired chromosome-21 status, support distinction from ML-DS and risk stratification.

Show evidence (3 references)

PMID:28112737 SUPPORT Human Clinical

"CBFA2T3-GLIS2 and NUP98-KDM5A, are missed by conventional karyotyping and therefore require split-signal FISH or RT-PCR for detection."

This directly supports targeted detection of cryptic fusion subgroups.

PMID:28112737 SUPPORT Human Clinical

"we recommend all pediatric non-DS-AMKL patients be tested for the presence of GATA1 mutations, CBFA2T3-GLIS2, KMT2Ar, and NUP98-KDM5A."

This supports the core molecular test panel.

PMID:28112737 SUPPORT Human Clinical

"Of the 93 patients for whom sufficient RNA was available ... 72.4% pediatric cases carried a structural variation (SV) predicted to lead to a fusion product by RNAseq ... RBM15-MKL1 (10.5%) ... Chimeric transcripts not previously described include several fusions involving genes within the HOX cluster"

The sequencing cohort supports broader RNA-based detection of recurrent and diverse fusion subgroups beyond the four-gene core recommendation.

📈

Progression

4

TAM Precursor State and Resolution

In infants with trisomy 21, GATA1-mutant TAM usually resolves over weeks. It is a precursor condition rather than an AMKL synonym.

Show evidence (1 reference)

PMID:21849481 SUPPORT Human Clinical

"Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively."

The prospective natural-history study documents spontaneous resolution.

Progression from TAM to ML-DS

A minority of TAM cases later develop ML-DS after acquiring additional lesions. Estimates differ with cohort definitions and era: 16% in COG A2971 and 23% in another prospective series, so no single universal percentage is encoded.

Show evidence (2 references)

PMID:21849481 SUPPORT Human Clinical

"Among all, AML subsequently occurred in 16% at a median of 441 days"

This gives a cohort-specific prospective progression estimate.

PMID:18182574 SUPPORT Human Clinical

"A total of 29 (23%) patients with TL subsequently developed ML-DS."

A second cohort demonstrates that progression rates vary by population and definition.

Molecularly Stratified Pediatric Relapse Risk

Pediatric Non-Down Syndrome AMKL

Pediatric non-DS AMKL outcome is strongly subgroup-dependent. CBFA2T3::GLIS2 and KMT2A rearrangements are adverse; GATA1-mutant and HOXr subgroups had favorable outcomes in the genomic cohort. These associations inform risk stratification but do not establish a universal transplant indication.

Show evidence (2 references)

PMID:28112737 SUPPORT Human Clinical

"Specifically, CBFA2T3-GLIS2 and KMT2Ar were found to have significantly inferior pEFS and pOS."

This supports molecularly stratified adverse outcomes.

PMID:28112737 SUPPORT Human Clinical

"GATA1 and HOXr subgroups carried significantly superior outcomes"

This supports the favorable-risk contrast in the same cohort.

Adult Treatment Resistance and Relapse

Adult AMKL has low complete-remission rates and short survival. Allogeneic transplantation can produce longer survival in selected patients, but post-transplant relapse remains frequent.

Show evidence (2 references)

PMID:37455345 SUPPORT Human Clinical

"Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks"

This quantifies treatment resistance and survival in the adult cohort.

PMID:37455345 SUPPORT Human Clinical

"cumulative incidence of relapse after allo-HSCT was high (62%)."

This qualifies transplantation as potentially curative but relapse-prone.

🔀

Differential Diagnoses

6

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

Transient Abnormal Myelopoiesis Not Yet Curated MONDO:0008040

Overlapping Features Neonatal trisomy-21-associated megakaryoblastic proliferation overlaps most directly with Down syndrome-associated AMKL.

Distinguishing Features

Restricted to newborns with trisomy 21 and typically resolves spontaneously.
Persistent or later overt leukemia rather than neonatal resolution raises concern for ML-DS.

Show evidence (1 reference)

PMID:21849481 SUPPORT Human Clinical

"Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution."

This establishes neonatal restriction and spontaneous resolution.

Acute Panmyelosis with Myelofibrosis Not Yet Curated MONDO:0019455

Overlapping Features A fibrotic acute myeloid neoplasm with substantial morphologic overlap.

Distinguishing Features

APMF shows trilineage hyperplasia with increased dysplastic megakaryocytes; AMKL-MF in the cited cohort showed higher marrow blasts, fewer mature megakaryocytes, rare megakaryocytic dysplasia, and chromosome-21 abnormality.

Show evidence (1 reference)

PMID:23693053 SUPPORT Human Clinical

"APMF showed hyperplasia of all three lineages, increase in megakaryocyte count with dysplasia and frequent abnormal karyotypes. AMKL-MF was associated with elevated BM blast counts, decreased BM megakaryocyte count with rare megakaryocytic dysplasia and chromosome 21 abnormality."

This directly compares two fibrotic acute myeloid presentations and refutes use of increased mature megakaryocytes as a general AMKL phenotype.

Primary Myelofibrosis MONDO:0009692

Overlapping Features A chronic myeloproliferative neoplasm that can overlap through fibrosis and splenomegaly.

Distinguishing Features

Rare peripheral/marrow blasts and JAK2 V617F favored PMF in the comparative cohort; AMKL requires an acute blast process with megakaryocytic-lineage markers.

Show evidence (1 reference)

PMID:23693053 SUPPORT Human Clinical

"PMF patients displayed splenomegaly, rare blasts in PB/BM, and JAK2 V617F mutation."

This identifies distinguishing features in the comparison cohort.

Myelodysplastic Syndrome with Myelofibrosis

Overlapping Features A fibrotic myelodysplastic presentation with cytopenias and trilineage dysplasia that can mimic AMKL with fibrosis. No exact MONDO binding is supplied for this composite label.

Distinguishing Features

Pancytopenia, trilineage dysplasia, and recurrent chromosome 5, 7, 12, or 17 abnormalities favored MDS-MF in the cited cohort.

Show evidence (1 reference)

PMID:23693053 SUPPORT Human Clinical

"MDS-MF patients showed pancytopenia, dysplasia in all three lineages and recurrent chromosomal abnormalities involving chromosome 5,7,12, and 17."

This defines distinguishing cohort features.

Megakaryocytic Blast Phase of Chronic Myeloid Leukemia

Overlapping Features CML blast phase can acquire a megakaryocytic phenotype and share platelet glycoprotein expression with de novo AMKL.

Distinguishing Features

Establish prior or concurrent CML/BCR::ABL1 context; the comparative adult series found more myeloperoxidase-positive blasts in megakaryocytic CML blast phase and more CD15 expression in de novo AMKL.

Show evidence (1 reference)

PMID:14968469 SUPPORT Human Clinical

"Leukemic cells of patients with AMegL expressed more frequently CD15 antigen than blast cells of those with MegBC-CML (83% and 37.5%; p < 0.05). In contrast, blast cells expressing myeloperoxidase were present in 50% and 10% of cases with MegBC-CML and AMegL, respectively"

Direct comparison documents immunophenotypic differences while reinforcing the need to establish the underlying CML context.

T-Lymphoblastic or Mixed-Lineage Acute Leukemia

Overlapping Features CBFA2T3::GLIS2-positive acute leukemia can coexpress T-lineage and megakaryocytic markers, creating a lineage-assignment pitfall.

Distinguishing Features

Bright CD56 with dim or negative HLA-DR, CD38, and CD45 (the RAM phenotype), megakaryocytic markers, and direct detection of CBFA2T3::GLIS2 support the fusion-positive AML spectrum.

Show evidence (1 reference)

PMID:37601875 SUPPORT Human Clinical

"CBFA2T3::GLIS2-positive acute leukemia with T/megakaryocytic markers could be misdiagnosed as T-lymphoblastic leukemia/lymphoma, early T-cell precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia, AML with minimal differentiation, or AML with myelodysplasia-related changes."

This directly identifies the diagnostic pitfall and its competing classifications.

📊

Related Datasets

2

Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia is Characterized by Distinct Genomic Subsets with Varying Outcomes ega:EGAS00001002183

Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While extremely rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML1-3. A significant proportion of pediatric AMKL cases occur in children with Down syndrome (DS). These patients have excellent outcomes and are characterized at the genomic level by a founding GATA1 mutation4-6. In contrast, AMKL in patients without DS (non-DS-AMKL) is frequently associated with poor outcomes.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Acute Megakaryoblastic Leukemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Single cell transcriptome analysis of pediatric acute megakaryoblastic leukemia ega:EGAS50000000612

Pediatric acute megakaryoblastic leukemia presenting fusion oncogene is generally associated with a poor prognosis. We performed single transcriptome analyses on bone marrow samples from pediatric acute megakaryoblastic leukemia patients presenting the ETO2-GLIS2 fusion oncogene.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Acute Megakaryoblastic Leukemia"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

🔬

Clinical Trials

2

ML-DS 2006 (EudraCT 2007-006219-2)

Prospective multicenter, open-label, nonrandomized treatment-reduction study in 170 children with ML-DS. Published final results support lowering etoposide and intrathecal prophylaxis and omitting maintenance without impairing excellent outcome. The publication reports ML-DS as a whole and does not provide morphology-stratified DS-AMKL trial results.

Show evidence (2 references)

PMID:28400376 SUPPORT Human Clinical

"We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial"

This defines the design and population of the published trial.

PMID:28400376 SUPPORT Human Clinical

"Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome."

This directly supports the trial-level conclusion that the tested reductions preserved outcome.

ML-DS 2018 (EudraCT 2018-002988-25) PHASE_III TERMINATED

Phase III study replacing intensity-reduced induction/reinduction with CPX-351 in ML-DS. It was halted after 35 enrollments because relapse was unexpectedly high. Toxicity was favorable, but 24-month EFS was inferior to the historical ML-DS 2006 result, so CPX-351 substitution is not encoded as recommended therapy. Results are ML-DS-wide rather than stratified by megakaryoblastic morphology.

Show evidence (3 references)

PMID:41118594 SUPPORT Human Clinical

"A total of 35 patients were enrolled until the trial was halted because of an unexpectedly high relapse rate."

This documents enrollment and early termination.

PMID:41118594 SUPPORT Human Clinical

"A per-protocol interim analysis revealed a significantly lower 24-month EFS when compared with the ML-DS 2006 trial (69% vs 90%; P< .001)."

The negative efficacy result prevents treatment recommendation despite favorable toxicity.

PMID:41118594 SUPPORT Human Clinical

"CPX-351 demonstrated a favorable toxicity profile with no treatment-related mortality."

This directly supports the favorable-toxicity qualification while the EFS result remains unfavorable.

🧫

Experimental Models

3

Trisomy-21 GATA1/STAG2 Double-Mutant iPSC Model IPSC_DERIVED_MODEL

Hematopoietic differentiation of gene-targeted trisomy-21 iPSCs models a progression-like, DS-ML-like immature megakaryocytic phenotype in vitro; it does not demonstrate overt AMKL in a patient or animal.

Organism

human NCBITaxon:9606

Cell source

Trisomy-21 induced pluripotent stem cells with engineered GATA1 and STAG2 mutations

Culture

Hematopoietic differentiation and megakaryocyte-lineage expansion

Publication

PMID:35203280

Pathograph links

Trisomy 21 and GATA1 Truncation Generate GATA1s Recapitulates GATA1s production in trisomy-21 hematopoietic progenitors.

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"We previously developed a model for TAM by introducing disease-specific GATA1 mutation in trisomy 21-induced pluripotent stem cells (iPSCs), leading to the production of N-terminally truncated short form of GATA1 (GATA1s)."

This directly supports the model link to trisomy-21-associated GATA1s production.

STAG2 Loss Enhances Immature Megakaryopoiesis in a Trisomy-21/GATA1s iPSC Model Models the incremental effect of engineered STAG2 loss beyond GATA1 mutation alone.

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"In this model, we used CRISPR/Cas9 to introduce a co-operating mutation in STAG2, a member of the cohesin complex recurrently mutated in DS-ML but not in TAM."

This directly identifies the engineered cooperating lesion in the iPSC system.

Immature Megakaryocytic Leukemic State Measures enhanced production of an immature megakaryocytic population in vitro.

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"Hematopoietic differentiation of GATA1 STAG2 double-mutant iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein, leading to enhanced production of immature megakaryocytic population compared to GATA1 mutant alone."

This directly supports the immature-megakaryocytic-state readout.

Findings

Megakaryocyte-specific lineage expansion of the double-mutant HSPCs resembled the DS-ML immunophenotype.

"Megakaryocyte-specific lineage expansion of the double-mutant HSPCs exhibited close resemblance to the DS-ML immunophenotype."

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"Megakaryocyte-specific lineage expansion of the double-mutant HSPCs exhibited close resemblance to the DS-ML immunophenotype."

This is the source's direct phenotypic characterization of the double-mutant lineage-expansion experiment.

Show evidence (1 reference)

PMID:35203280 SUPPORT In Vitro

"In conclusion, we developed a DS-ML model via hematopoietic differentiation of gene-targeted iPSCs bearing trisomy 21."

The publication explicitly identifies the engineered iPSC system as a DS-ML model.

NUP98-KDM5A Cord-Blood HSPC Model PRIMARY_CELL_CULTURE

Lentiviral NUP98::KDM5A expression in human cord-blood HSPCs creates a synthetic model of fusion-driven maturation arrest and progenitor persistence.

Organism

human NCBITaxon:9606

Cell source

Human cord-blood hematopoietic stem and progenitor cells

Culture

Lentiviral transduction in optimized hematopoietic culture

Publication

PMID:31698461

Pathograph links

NUP98::KDM5A Sustains Progenitor Capacity and Maturation Arrest Models the fusion-driven leukemic state.

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions."

This directly supports the fusion-specific model link.

Immature Megakaryocytic Leukemic State Recapitulates maturation arrest and sustained progenitor capacity.

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions."

The engineered-cell result directly supports the model's immature-state readout.

Findings

NUP98::KDM5A induced maturation arrest and long-term progenitor capacity.

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions."

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions."

This is the source's direct in-vitro finding for the engineered HSPCs.

Show evidence (1 reference)

PMID:31698461 SUPPORT In Vitro

"we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and progenitor cells using a lentiviral-based approach to create physiopathologically relevant disease models."

This directly describes the engineered human-cell model.

CBFA2T3-GLIS2 Cord-Blood HSPC Endothelial Coculture CO_CULTURE

Fusion-transduced human cord-blood HSPCs maintained with endothelial cells recapitulate fusion-positive AML transcriptional, morphologic, and immunophenotypic features.

Organism

human NCBITaxon:9606

Cell source

Human cord-blood hematopoietic stem and progenitor cells plus endothelial cells

Culture

Endothelial cell coculture

Publication

PMID:36136600

Pathograph links

Immature Megakaryocytic Leukemic State Recapitulates fusion-positive AML morphology and immunophenotype.

Show evidence (1 reference)

PMID:36136600 SUPPORT In Vitro

"the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML)"

This directly supports the coculture's fusion-positive cellular-state readout without importing BMP results from a different model.

Findings

The endothelial niche supports transformation of fusion-transduced cord-blood HSPCs.

"the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML)"

Show evidence (1 reference)

PMID:36136600 SUPPORT In Vitro

"the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML)"

This is the directly reported coculture transformation finding.

Show evidence (1 reference)

PMID:36136600 SUPPORT In Vitro

"the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML)"

This directly describes the human endothelial-coculture model.

🐁

Animal Models

4

Ott-Mal knock-in donor marrow retrovirally transduced ex vivo with MPLW515L and transplanted into lethally irradiated WT C57BL/6 recipients mouse Transduction/transplant cooperation model

Primary marrow from nonleukemic Ott-Mal knock-in donors is transduced ex vivo with MPLW515L and transplanted into lethally irradiated wild-type recipients. This is a two-hit transduction/transplant cooperation model, not a mouse carrying an inherited activating Mpl allele.

Species

mouse

Genotype

Ott-Mal knock-in donor marrow retrovirally transduced ex vivo with MPLW515L and transplanted into lethally irradiated WT C57BL/6 recipients

Background

C57BL/6

Genes

RBM15 hgnc:14959 MRTFA hgnc:14334 MPL hgnc:7217

Show evidence (2 references)

PMID:19287095 SUPPORT Model Organism

"BM cells from 2-month-old nonleukemic OM or WT littermates ... retroviruses harboring the MPL W515L allele ... lethally irradiated WT C57BL/6 recipients"

This directly identifies the ex-vivo transduction and recipient-transplant construction of the cooperation model.

PMID:19287095 SUPPORT Model Organism

"cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block,..."

This supports the associated model phenotypes while retaining the requirement for forced MPL cooperation.

Human pediatric AMKL patient-cell xenotransplant mouse Patient-derived xenograft

Patient-derived pediatric non-DS AMKL xenografts reproduce human leukemic growth and provide an in-vivo platform for molecular discovery and preclinical drug screening.

Species

mouse

Genotype

Human pediatric AMKL patient-cell xenotransplant

Background

NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG)

Show evidence (1 reference)

PMID:23045605 SUPPORT Model Organism

"Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors."

This establishes the patient-derived xenograft as a screening platform, not a clinical treatment recommendation.

NUP98-KDM5A-transduced human cord-blood HSPC xenograft mouse Synthetic human xenograft model

Synthetic NUP98::KDM5A human-cell xenografts can generate AMKL-like disease and expose preclinical signaling vulnerabilities.

Species

mouse

Genotype

NUP98-KDM5A-transduced human cord-blood HSPC xenograft

Background

immunodeficient

Genes

NUP98 hgnc:8068 KDM5A hgnc:9886

Show evidence (1 reference)

PMID:31698461 SUPPORT Model Organism

"Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient mice led to multiple subtypes of leukemia, including AMKL, that phenocopy human disease phenotypically and molecularly."

The synthetic xenograft phenocopies human NUP98::KDM5A AMKL.

CBFA2T3-GLIS2-transduced human cord-blood HSPC xenograft mouse Synthetic human xenograft model

Fusion-transduced human cord-blood progenitors generate aggressive CBFA2T3::GLIS2-positive leukemia in xenografts and support preclinical target evaluation.

Species

mouse

Genotype

CBFA2T3-GLIS2-transduced human cord-blood HSPC xenograft

Background

NSG-SGM3

Genes

CBFA2T3 hgnc:1537 GLIS2 hgnc:29450

Show evidence (1 reference)

PMID:36136600 SUPPORT Model Organism

"the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML)..."

The engineered human cells induce aggressive fusion-positive leukemia in vivo.

{ }

Source YAML

click to show

name: Acute Megakaryoblastic Leukemia
creation_date: "2026-05-08T12:00:00Z"
description: >-
  Acute megakaryoblastic leukemia (AMKL, historically FAB M7) is an acute
  myeloid leukemia defined by megakaryocytic differentiation of the blasts.
  The disease occurs in three clinically and biologically distinct settings:
  children with Down syndrome, children without Down syndrome, and adults.
  Down syndrome-associated disease follows a multistep sequence involving
  constitutional trisomy 21, a GATA1 truncating mutation that produces GATA1s,
  transient abnormal myelopoiesis, and additional somatic lesions. Pediatric
  non-Down syndrome AMKL instead comprises recurrent molecular subgroups,
  including RBM15::MRTFA, CBFA2T3::GLIS2, NUP98::KDM5A, KMT2A, diverse HOX
  rearrangements, and a GATA1-mutant subgroup usually carrying acquired gain of
  chromosome 21. Adult AMKL has a different, adverse genomic landscape and
  poor treatment response. Diagnosis requires morphology together with
  immunophenotypic evidence of megakaryocytic differentiation.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Rare Disease
parents:
- acute myeloid leukemia
disease_term:
  preferred_term: acute megakaryoblastic leukemia
  term:
    id: MONDO:0018872
    label: acute megakaryoblastic leukemia
has_subtypes:
- name: Down Syndrome-Associated AMKL
  display_name: Acute Megakaryoblastic Leukemia in Down Syndrome
  description: >-
    The megakaryoblastic leukemia phenotype arising in young children with Down
    syndrome. Acquired GATA1s-generating mutations are highly recurrent. This is
    represented within the broader ML-DS clinical category, whose published
    treatment cohorts are not always stratified by megakaryoblastic morphology.
    TAM is a distinct neonatal precursor condition rather than overt AMKL.
  subtype_term:
    preferred_term: acute megakaryoblastic leukemia in down syndrome
    term:
      id: MONDO:0020526
      label: acute megakaryoblastic leukemia in down syndrome
  evidence:
  - reference: PMID:12172547
    reference_title: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukemic cells from every individual with DS-AMKL that we examined contain
      mutations in GATA1
    explanation: >-
      This directly supports the DS-AMKL phenotype and its recurrent acquired
      GATA1 mutation.
  - 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: >-
      Myeloid proliferations associated with Down syndrome, typically associated
      with somatic exon 2 or 3 GATA1 mutation, continue to encompass two clonal
      conditions that arise in children with constitutional trisomy 21:
      transient abnormal myelopoiesis (TAM), which is conﬁned to the ﬁrst 6
      months of life and myeloid leukaemia of Down syndrome (ML-DS).
    explanation: >-
      WHO separates neonatal TAM from ML-DS while placing both in the
      trisomy-21/GATA1 disease spectrum.
- name: Non-Down Syndrome AMKL
  display_name: Acute Megakaryoblastic Leukemia Without Down Syndrome
  description: >-
    AMKL without constitutional Down syndrome. This age-spanning umbrella
    includes pediatric non-Down-syndrome AMKL and adult AMKL, which have
    different genomic architectures and treatment outcomes.
  subtype_term:
    preferred_term: acute megakaryoblastic leukemia without down syndrome
    term:
      id: MONDO:0018004
      label: acute megakaryoblastic leukemia without down syndrome
  children:
  - Pediatric Non-Down Syndrome AMKL
  - Adult AMKL
  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: >-
      which arises within three clinical groups: children with Down syndrome,
      children without Down syndrome, and adults.
    explanation: >-
      WHO distinguishes children without Down syndrome from adults while both
      remain within the broader non-Down-syndrome umbrella.
- name: Pediatric Non-Down Syndrome AMKL
  display_name: Pediatric Acute Megakaryoblastic Leukemia Without Down Syndrome
  description: >-
    Pediatric AMKL without constitutional Down syndrome. It is composed of
    recurrent, usually mutually exclusive molecular subgroups with different
    outcomes. These are molecular subgroups among AML cases with
    megakaryoblastic differentiation and are not all formal WHO disease classes.
    No exact pediatric-umbrella ontology class is bound here.
  children:
  - RBM15::MRTFA-Rearranged AMKL
  - CBFA2T3::GLIS2-Positive AMKL
  - NUP98::KDM5A-Positive AMKL
  - KMT2A-Rearranged AMKL
  - HOX-Rearranged AMKL
  - GATA1-Mutant Non-Down Syndrome AMKL
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy
      that can be divided into seven subgroups with varying outcomes.
    explanation: >-
      Genomic profiling establishes pediatric non-DS AMKL as a collection of
      distinct molecular subgroups.
- name: RBM15::MRTFA-Rearranged AMKL
  display_name: Infant AMKL with t(1;22) RBM15::MRTFA
  description: >-
    An infant-predominant non-DS AMKL subgroup defined by
    t(1;22)(p13;q13), which creates the RBM15::MRTFA fusion (historically
    RBM15-MKL1 or OTT-MAL).
  subtype_term:
    preferred_term: megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)
    term:
      id: MONDO:0018436
      label: megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)
  evidence:
  - reference: PMID:11431691
    reference_title: "Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we show this chromosomal rearrangement to result in the fusion of two
      novel genes, RNA-binding motif protein-15 (RBM15), an RNA recognition
      motif-encoding gene with homology to Drosophila spen, and Megakaryoblastic
      Leukemia-1 (MKL1)
    explanation: >-
      The original molecular report identifies the two partners created by
      t(1;22).
- name: CBFA2T3::GLIS2-Positive AMKL
  description: >-
    A high-risk pediatric non-DS AMKL subgroup with a cryptic chromosome 16
    inversion. The same fusion also occurs in AML with other morphologies, so
    the broader CBFA2T3::GLIS2-positive AML ontology class is not used as an
    exact AMKL subtype binding here.
  evidence:
  - reference: PMID:31719049
    reference_title: "Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of this fusion was highly associated with adverse outcome
      (P < 0.001) across all morphologic classifications.
    explanation: >-
      The fusion is prognostically adverse but is not restricted to
      megakaryoblastic morphology.
- name: NUP98::KDM5A-Positive AMKL
  description: >-
    A recurrent pediatric non-DS molecular subgroup defined by the NUP98::KDM5A
    fusion. Cohort estimates trend toward adverse outcome, but small numbers
    preclude treating that effect as independently established. Depending on the
    classification framework, a fusion-defined AML category may take precedence
    while megakaryoblastic differentiation remains clinically relevant.
  subtype_term:
    preferred_term: childhood acute megakaryoblastic leukemia with NUP98-KDM5A
    term:
      id: NCIT:C132111
      label: Childhood Acute Megakaryoblastic Leukemia with NUP98-KDM5A
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recurrent and mutually exclusive chimeric fusion oncogenes have been
      detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene
      rearrangements, most commonly NUP98-KDM5A.
    explanation: >-
      This identifies NUP98::KDM5A as the predominant NUP98 rearrangement in
      pediatric AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NUP98-KDM5A cases also demonstrated a trend towards poor outcomes, however
      due to small numbers this failed to reach statistical significance.
    explanation: >-
      This supports an adverse trend while preserving the cohort's statistical
      uncertainty.
- name: KMT2A-Rearranged AMKL
  description: >-
    A mutually exclusive founding genomic subgroup among pediatric non-DS AML
    cases with megakaryoblastic differentiation. KMT2A-rearranged AML can be a
    genetically defined AML category rather than a formal AMKL child class. The
    subgroup is associated with a HOX transcriptional program and adverse outcome.
  evidence:
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in
      6%. These aberrations were mutually exclusive.
    explanation: >-
      This supports KMT2A rearrangement as a mutually exclusive defining
      subgroup rather than a generic cooperating lesion.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, CBFA2T3-GLIS2 and KMT2Ar were found to have significantly
      inferior pEFS and pOS.
    explanation: >-
      This directly supports the adverse outcome association in the genomic
      cohort.
  - reference: PMID:23045605
    reference_title: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One subgroup of patients presented with MLL or NUP98 fusion genes leading
      to up-regulation of the HOX A cluster genes.
    explanation: >-
      Patient expression data support the KMT2A/MLL-associated HOXA program.
- name: HOX-Rearranged AMKL
  description: >-
    A pediatric non-DS molecular subgroup among AML cases with megakaryoblastic
    differentiation, with diverse rearrangements involving HOX loci, a shared
    HOX expression program, and enrichment for activating MPL mutations.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, fusions involving a HOX cluster gene (HOXr) occurred in 14%
      of patients within this cohort
    explanation: >-
      This defines and quantifies the HOX-rearranged subgroup in the reported
      pediatric cohort.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HOXr cases were found to be significantly enriched in activating MPL mutations
    explanation: >-
      This directly supports the subgroup's recurrent MPL association.
- name: GATA1-Mutant Non-Down Syndrome AMKL
  description: >-
    A distinct pediatric molecular subgroup without clinical Down syndrome or
    full constitutional trisomy 21, in which somatic GATA1 truncation usually
    co-occurs with acquired amplification of chromosome 21 material and produces
    a Down syndrome-like expression signature. Rare mosaic trisomy 21 must be
    specifically assessed rather than assumed absent from phenotype alone.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine of ten GATA1 mutant cases had amplifications in the DSCR
    explanation: >-
      This directly corrects the older claim that GATA1 mutation is absent from
      non-DS AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had non-hematopoietic tissue available for analysis and was
      found to be germline mosaic for trisomy 21
    explanation: >-
      This documents the mosaic-trisomy exception and the need for appropriate
      constitutional testing.
- name: Adult AMKL
  display_name: Acute Megakaryoblastic Leukemia in Adults
  description: >-
    Adult AMKL is uncommon and biologically distinct from pediatric disease.
    Recurrent pediatric fusion subgroups are generally absent; adult cohorts
    instead show adverse cytogenetics and recurrent alterations in genes such
    as TET2, TP53, JAK2, PTPN11, and RUNX1.
  subtype_term:
    preferred_term: acute megakaryoblastic leukemia in adult
    term:
      id: MONDO:0971091
      label: acute megakaryoblastic leukemia in adult
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%),
      PTPN11 (19%) and RUNX1 (15%).
    explanation: >-
      A dedicated adult cohort establishes a genomic profile distinct from the
      recurrent pediatric fusions.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, in the adult cohort (n=24) which lacked recurrent fusion genes
    explanation: >-
      This direct pediatric-adult comparison supports the stated absence of
      recurrent pediatric fusion groups in that adult cohort.
mechanistic_hypotheses:
- hypothesis_group_id: ml_ds_multistep_leukemogenesis
  hypothesis_label: Multistep Leukemogenesis in Down Syndrome
  status: CANONICAL
  applies_to_subtypes:
  - Down Syndrome-Associated AMKL
  description: >-
    Trisomy 21 and a GATA1s-generating mutation establish the TAM clone;
    additional somatic lesions are implicated in progression to overt ML-DS.
  evidence:
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GATA1s, together with trisomy 21, is sufficient to develop a pre-leukemic
      condition called transient abnormal myelopoiesis (TAM).
    explanation: >-
      This is background synthesis in the model paper, not a result of the iPSC
      experiment itself.
  - reference: PMID:21849481
    reference_title: "Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among all, AML subsequently occurred in 16% at a median of 441 days
    explanation: >-
      Prospective natural history shows that only a subset of TAM cases later
      develop leukemia.
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hematopoietic differentiation of GATA1&nbsp;STAG2 double-mutant iPSC lines
      confirmed GATA1s expression and the loss of functional STAG2 protein,
      leading to enhanced production of immature megakaryocytic population
      compared to GATA1 mutant alone.
    explanation: >-
      This models one cooperating lesion that intensifies an immature
      megakaryocytic phenotype without proving overt leukemic conversion.
- hypothesis_group_id: pediatric_non_ds_genomic_subgroups
  hypothesis_label: Fusion-Defined Pediatric Non-DS AMKL Subgroups
  status: CANONICAL
  applies_to_subtypes:
  - Pediatric Non-Down Syndrome AMKL
  description: >-
    Pediatric non-DS AMKL comprises mutually exclusive genomic subgroups whose
    founding lesions define distinct transcriptional programs, cooperating
    alterations, and clinical risks within an immature megakaryocytic leukemic
    state.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These subgroups are characterized by chimeric oncogenes with cooperating
      mutations in epigenetic and kinase signaling genes.
    explanation: >-
      Large-scale sequencing supports a subgroup model with founding fusions
      and subgroup-specific cooperating lesions.
- hypothesis_group_id: adult_amkl_distinct_genomic_model
  hypothesis_label: Distinct Adult AMKL Genomic Model
  status: CANONICAL
  applies_to_subtypes:
  - Adult AMKL
  description: >-
    Adult AMKL is not simply an age-shifted pediatric fusion leukemia; it is
    characterized by adverse cytogenetics, a different mutation spectrum, and
    marked treatment resistance.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, in the adult cohort (n=24) which lacked recurrent fusion
      genes, the most highly recurrent mutations were in TP53 (20.8%), cohesin
      genes (16.7%), splicing factor genes (16.7%), ASXL genes (16.7%) and
      DNMT3A (12.5%)
    explanation: >-
      Direct pediatric-adult comparison supports a separate adult genomic
      model.
pathophysiology:
- name: Trisomy 21 and GATA1 Truncation Generate GATA1s
  description: >-
    In the usual Down syndrome-associated sequence, an acquired GATA1 mutation
    introduces a premature stop in the N-terminal activation domain. Full-length
    GATA1 is lost while a shorter downstream-initiated GATA1s protein is
    retained. The trisomy-21 fetal hematopoietic context and GATA1s cooperate to
    establish the precursor clone.
  subtypes:
  - Down Syndrome-Associated AMKL
  genes:
  - preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  evidence:
  - reference: PMID:12172547
    reference_title: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations prevent synthesis of full-length GATA1, but not synthesis
      of a shorter variant that is initiated downstream.
    explanation: >-
      This directly establishes the protein-level consequence of the
      GATA1-truncating mutations.
  downstream:
  - target: GATA1s-Driven Transient Abnormal Myelopoiesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - ml_ds_multistep_leukemogenesis
    description: >-
      In a trisomy-21 hematopoietic background, GATA1s is sufficient to produce
      the preleukemic TAM state in experimental models.
    evidence:
    - reference: PMID:35203280
      reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        GATA1s, together with trisomy 21, is sufficient to develop a pre-leukemic
        condition called transient abnormal myelopoiesis (TAM).
      explanation: >-
        This engineered-cell model directly supports the preleukemic transition.
- name: GATA1s-Driven Transient Abnormal Myelopoiesis
  description: >-
    TAM is a neonatal clonal myeloid proliferation restricted to infants with
    trisomy 21 and GATA1s. It often resolves spontaneously and is not itself
    AMKL, but it is the recognized precursor from which a subset of ML-DS cases
    later emerge.
  subtypes:
  - Down Syndrome-Associated AMKL
  genes:
  - preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  evidence:
  - reference: PMID:14636651
    reference_title: Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We detected GATA1 mutations in TMD blasts from every infant examined.
    explanation: >-
      This establishes GATA1 mutation as an early event already present in the
      transient precursor clone.
  - reference: PMID:21849481
    reference_title: "Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among those solely observed, peripheral blasts and all other TMD symptoms
      cleared at a median of 36 and 49 days from diagnosis, respectively.
    explanation: >-
      Prospective observation documents the characteristic spontaneous
      resolution of TAM.
- name: STAG2 Loss Enhances Immature Megakaryopoiesis in a Trisomy-21/GATA1s iPSC Model
  description: >-
    In gene-targeted trisomy-21/GATA1-mutant iPSCs, STAG2 loss enhanced production
    of an immature megakaryocytic population relative to GATA1 mutation alone.
    This is one progression model; it does not establish that STAG2 loss alone
    converts TAM into overt ML-DS or AMKL in vivo.
  subtypes:
  - Down Syndrome-Associated AMKL
  genes:
  - preferred_term: STAG2
    term:
      id: hgnc:11355
      label: STAG2
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  evidence:
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hematopoietic differentiation of GATA1&nbsp;STAG2 double-mutant iPSC lines
      confirmed GATA1s expression and the loss of functional STAG2 protein,
      leading to enhanced production of immature megakaryocytic population
      compared to GATA1 mutant alone.
    explanation: >-
      Sequential editing shows that STAG2 loss intensifies the immature
      megakaryocytic state beyond GATA1s alone.
- name: RBM15::MRTFA Fusion Deregulates RBPJ Transcription
  description: >-
    The t(1;22) fusion joins RBM15 to MRTFA (formerly MKL1). In a knock-in mouse
    model the fusion deregulates RBPJ-mediated canonical Notch transcription
    and abnormal fetal megakaryopoiesis; cooperation with activating MPL is
    required for short-latency model disease.
  subtypes:
  - RBM15::MRTFA-Rearranged AMKL
  genes:
  - preferred_term: RBM15
    term:
      id: hgnc:14959
      label: RBM15
  - preferred_term: MRTFA
    term:
      id: hgnc:14334
      label: MRTFA
  gene_products:
  - preferred_term: RBM15/MKL1 fusion protein
    term:
      id: NCIT:C99702
      label: RBM15/MKL1 Fusion Protein
  evidence:
  - reference: PMID:19287095
    reference_title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OTT-MAL expression deregulated transcriptional activity of the canonical
      Notch signaling pathway transcription factor recombination signal binding
      protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal
      megakaryopoiesis.
    explanation: >-
      The knock-in model directly supports RBPJ/Notch transcriptional
      dysregulation.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      Fusion-driven RBPJ dysregulation, together with engineered activating MPL
      signaling, produced an immature megakaryoblastic leukemia in the model.
    evidence:
    - reference: PMID:19287095
      reference_title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cooperation between OTT-MAL and an activating mutation of the
        thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL)
        efficiently induced a short-latency AMKL that recapitulated all the
        features of human AMKL, including megakaryoblast hyperproliferation and
        maturation block
      explanation: >-
        The two-hit model supports an immature megakaryoblastic state but does
        not isolate the effect of RBM15::MRTFA alone.
- name: CBFA2T3::GLIS2 Induces BMP Signaling and Progenitor Self-Renewal
  description: >-
    The cryptic inv(16)(p13.3q24.3) CBFA2T3::GLIS2 fusion increases BMP
    signaling and self-renewal in experimental hematopoietic progenitors. Human
    transcriptomic studies also associate the fusion with Hippo, TGF-beta, and
    Hedgehog pathway dysregulation, but those associations are not modeled here
    as individually proven causal edges.
  subtypes:
  - CBFA2T3::GLIS2-Positive AMKL
  genes:
  - preferred_term: CBFA2T3
    term:
      id: hgnc:1537
      label: CBFA2T3
  - preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  biological_processes:
  - preferred_term: BMP signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  - preferred_term: stem cell population maintenance
    modifier: INCREASED
    term:
      id: GO:0019827
      label: stem cell population maintenance
  gene_products:
  - preferred_term: CBFA2T3/GLIS2 fusion protein
    term:
      id: NCIT:C105820
      label: CBFA2T3/GLIS2 Fusion Protein
  evidence:
  - reference: PMID:23153540
    reference_title: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells
      induced bone morphogenic protein (BMP) signaling and resulted in a marked
      increase in the self-renewal capacity of hematopoietic progenitors.
    explanation: >-
      Cross-species functional experiments directly support BMP activation and
      increased progenitor self-renewal.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      Fusion-induced self-renewal and transformation can produce an immature
      leukemic state, although the cited experiment does not establish every
      component of megakaryocytic lineage specification.
    evidence:
    - reference: PMID:31719049
      reference_title: "Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        transduction of cord blood stem cells with this fusion was sufficient
        for malignant transformation.
      explanation: >-
        Human cord-blood transformation supports leukemogenicity but only
        partially supports the lineage-specific clinical state.
- name: NUP98::KDM5A Sustains Progenitor Capacity and Maturation Arrest
  description: >-
    NUP98::KDM5A is a potent driver of maturation arrest and long-term
    proliferative/progenitor capacity in engineered human hematopoietic cells.
    Model systems also show JAK-STAT upregulation and drug sensitivity, but
    these preclinical dependencies are not established clinical treatments.
  subtypes:
  - NUP98::KDM5A-Positive AMKL
  genes:
  - preferred_term: NUP98
    term:
      id: hgnc:8068
      label: NUP98
  - preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  gene_products:
  - preferred_term: NUP98/KDM5A fusion protein
    term:
      id: NCIT:C105816
      label: NUP98/KDM5A Fusion Protein
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest,
      sustaining long-term proliferative and progenitor capacities of engineered
      cells in optimized culture conditions.
    explanation: >-
      The engineered human-cell system directly supports maturation arrest and
      persistent progenitor capacity.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      NUP98::KDM5A directly causes maturation arrest in engineered cells, while
      the path from that state to megakaryocytic leukemia remains model- and
      context-dependent.
    evidence:
    - reference: PMID:31698461
      reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient
        mice led to multiple subtypes of leukemia, including AMKL, that phenocopy
        human disease phenotypically and molecularly.
      explanation: >-
        Xenotransplantation shows that the engineered state can generate AMKL,
        but also other leukemia phenotypes.
- name: KMT2A- and NUP98-Rearranged HOXA Program
  description: >-
    KMT2A (historically MLL) and NUP98 fusions define distinct pediatric
    subgroups but converge at the level of HOXA-cluster upregulation. This node
    models the shared transcriptional program without treating KMT2A as a
    cooperating lesion of another fusion subgroup.
  subtypes:
  - KMT2A-Rearranged AMKL
  - NUP98::KDM5A-Positive AMKL
  genes:
  - preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  - preferred_term: NUP98
    term:
      id: hgnc:8068
      label: NUP98
  evidence:
  - reference: PMID:23045605
    reference_title: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One subgroup of patients presented with MLL or NUP98 fusion genes leading
      to up-regulation of the HOX A cluster genes.
    explanation: >-
      Patient genomic and expression data support a shared HOXA program in
      KMT2A/MLL- and NUP98-rearranged disease.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      The fusion-associated HOXA program is present in these AMKL cohorts, but
      the expression association alone does not establish a causal route to the
      megakaryocytic leukemic phenotype.
    evidence:
    - reference: PMID:28112737
      reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Combined with KMT2Ar and NUP98-KDM5A, chimeric oncogenes known to
        upregulate HOX cluster genes, roughly half of pediatric non-DS-AMKL
        patients carry a HOX gene expression program.
      explanation: >-
        Human expression profiling supports the shared program; the edge to
        maturation arrest remains mechanistically indirect.
- name: HOX Rearrangement and MPL/JAK-STAT Cooperation
  description: >-
    HOX-rearranged pediatric AMKL is enriched for activating MPL mutations.
    Experimental co-expression of a HOX rearrangement and mutant MPL produces a
    cytokine-independent growth advantage with phosphorylated JAK2 and STAT5,
    supporting subgroup-specific signaling cooperation.
  subtypes:
  - HOX-Rearranged AMKL
  genes:
  - preferred_term: MPL
    term:
      id: hgnc:7217
      label: MPL
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HOXr cases were found to be significantly enriched in activating MPL mutations
    explanation: >-
      Human tumors establish enrichment of activating MPL mutations in this
      subgroup.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Activated JAK-STAT signaling as determined by phosphorylated JAK2 and STAT5
      was found in HOXr cells containing a MPL mutation
    explanation: >-
      Cytokine-withdrawal experiments provide a functional signaling readout for
      HOXr/MPL cooperation.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      Activating MPL supplies a JAK-STAT-dependent growth advantage to the
      HOX-rearranged experimental system and may contribute to leukemic-cell
      persistence.
    evidence:
    - reference: PMID:28112737
      reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        a growth advantage was identified in cells containing both a HOXr and a
        MPL mutation
      explanation: >-
        The co-expression experiment supports a cooperative growth effect, not
        a complete lineage-specification mechanism.
- name: Non-DS GATA1 Mutation Cooperates with Chromosome 21 Gain
  description: >-
    A non-DS pediatric subgroup carries somatic GATA1 truncation without
    constitutional trisomy 21. Most reported cases had acquired amplification
    of the Down syndrome critical region and a transcriptional profile closely
    resembling DS-AMKL.
  subtypes:
  - GATA1-Mutant Non-Down Syndrome AMKL
  genes:
  - preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine of ten GATA1 mutant cases had amplifications in the DSCR
    explanation: >-
      This establishes recurrent acquired chromosome-21 amplification in
      GATA1-mutant non-DS disease.
  downstream:
  - target: Immature Megakaryocytic Leukemic State
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - pediatric_non_ds_genomic_subgroups
    description: >-
      GATA1 mutation and acquired chromosome-21 gain are associated with a
      DS-AMKL-like expression program, but the cohort does not resolve a causal
      path to the clinical blast phenotype.
    evidence:
    - reference: PMID:28112737
      reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        this signature was strongly correlated with that found in DS-AMKL
      explanation: >-
        Human expression correlation supports biologic similarity but not a
        resolved causal mechanism.
- name: Adult Adverse Genomic Landscape and Therapy Resistance
  description: >-
    Adult AMKL cohorts show adverse cytogenetics, frequent chromosome 1q
    aberrations, and recurrent mutations unlike the pediatric fusion spectrum.
    These observations are clinically associated with low remission rates and
    short survival; which lesions are causal for megakaryoblastic differentiation
    remains unresolved.
  subtypes:
  - Adult AMKL
  genes:
  - preferred_term: TET2
    term:
      id: hgnc:25941
      label: TET2
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  - preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  - preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete remission rate in 33 patients receiving intensive chemotherapy
      was 33% and median overall survival (OS) was 33 weeks
    explanation: >-
      The adult cohort documents profound treatment resistance and poor outcome.
- name: Immature Megakaryocytic Leukemic State
  description: >-
    AMKL is defined by an acute leukemic blast population with megakaryocytic
    differentiation. The cells can retain multilineage potential; available
    human evidence does not establish one universal maturation block or require
    assignment to a fully committed megakaryocyte-erythroid progenitor.
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:8069184
    reference_title: Phenotypic characteristics of acute megakaryocytic leukemia and transient abnormal myelopoiesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The target cells of AMKL and TAM are immature cells close to stem cells
      which are capable of differentiating into lineage cells such as
      megakaryocytes, erythrocytes and myeloid cells.
    explanation: >-
      This supports an immature, multilineage-capable cell state while avoiding
      an unsupported universal cell-of-origin claim.
  - 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: >-
      Blasts express at least one or more of the platelet glycoproteins: CD41
      (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)
    explanation: >-
      WHO anchors the clinical disease state in megakaryocytic-lineage marker
      expression.
  downstream:
  - target: PDGF-Associated Marrow Fibrosis
    causal_link_type: UNKNOWN
    description: >-
      PDGF-BB positivity in megakaryoblasts is associated with marrow fibrosis;
      direction and causality are unresolved.
    evidence:
    - reference: PMID:23530558
      reference_title: "Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The PDGF-positive cases showed various degrees of fibrosis, while the
        negative cases showed no evidence of fibrosis.
      explanation: >-
        This directly supports a human association between PDGF positivity and
        fibrosis.
  - target: Extramedullary Leukemic Infiltration
    causal_link_type: UNKNOWN
    description: >-
      Megakaryoblastic tissue infiltration co-occurs with the leukemic blast
      state in infant t(1;22) disease; the observational series does not establish
      a direct causal transition.
    evidence:
    - reference: PMID:1510033
      reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunophenotyping of peripheral blood mononuclear cells was helpful in
        identifying the blasts as belonging to the megakaryoblastic lineage.
        Using a panel of mononclonal antibodies, it was also possible to confirm
        the nature of the infiltration in paraffin sections
      explanation: >-
        Tissue immunophenotyping confirmed megakaryoblastic infiltration in the
        infant t(1;22) series.
  - target: Anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Anemia accompanies the leukemic marrow state, but the cached clinical
      evidence does not resolve the relative effects of marrow replacement,
      fibrosis, inflammation, and treatment.
    evidence:
    - reference: PMID:23530558
      reference_title: "Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All cases had anaemia, but leukocyte and platelet counts varied.
      explanation: >-
        All 18 cases in this mixed idiopathic/secondary cohort had anemia.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Low platelet counts are common in reported pediatric cohorts, but AMKL can
      also present with normal counts and the mechanism is not captured by one
      universal causal route.
    evidence:
    - reference: PMID:33812402
      reference_title: "[Analysis of Clinical Characteristics and Prognosis in Children with Acute Megakaryoblastic Leukemia without Down Syndrome]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the median hemoglobin was 67 g/L and median platelet was 16×109/L.
      explanation: >-
        This reports a low median platelet count in a 19-child non-DS cohort
        without asserting an AMKL-wide frequency.
- name: PDGF-Associated Marrow Fibrosis
  description: >-
    AMKL marrow commonly shows reticulin fibrosis. In a clinicopathologic series,
    PDGF-BB staining in megakaryoblasts and some fibroblasts tracked with the
    presence of fibrosis, supporting a growth-factor-associated stromal response
    while leaving additional mediators unresolved.
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:23530558
    reference_title: "Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine of the 11 cases examined immunohistochemically were positive for
      platelet-derived growth factor (PDGF)(-BB), especially megakaryoblasts and
      a few fibroblasts.
    explanation: >-
      This localizes PDGF-BB immunoreactivity to megakaryoblasts and some
      fibroblasts in the reported cases.
  downstream:
  - target: Myelofibrosis
    causal_link_type: UNKNOWN
    description: >-
      PDGF positivity and myelofibrosis co-occurred in the examined cases; this
      edge records the unresolved association rather than a proven direct effect.
    evidence:
    - reference: PMID:23530558
      reference_title: "Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The PDGF-positive cases showed various degrees of fibrosis, while the
        negative cases showed no evidence of fibrosis.
      explanation: >-
        This is an association in a clinicopathologic series, not proof that PDGF
        directly causes the phenotype.
- name: Extramedullary Leukemic Infiltration
  description: >-
    Leukemic megakaryoblasts may form cohesive infiltrates in liver, lymph node,
    and other tissues. This is particularly well documented in infant
    t(1;22) AMKL and can resemble a nonhematopoietic small-round-cell tumor.
  subtypes:
  - RBM15::MRTFA-Rearranged AMKL
  evidence:
  - reference: PMID:1510033
    reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biopsy specimens of the liver and lymph node were suggestive of a
      nonhematopoietic malignant condition because of the cohesiveness of the
      tumor cells, stromal fibrosis, and the prominent sinusoidal and vascular
      pattern of infiltration.
    explanation: >-
      This describes the characteristic tissue infiltration pattern in the
      infant t(1;22) cohort.
  downstream:
  - target: Hepatosplenomegaly
    causal_link_type: UNKNOWN
    description: >-
      Tissue infiltration and liver/spleen enlargement co-occurred in the six
      reported infants; direction and causality were not tested.
    evidence:
    - reference: PMID:1510033
      reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All the patients had hepatosplenomegaly and anemia
      explanation: >-
        All six infants in the reported t(1;22) series had
        hepatosplenomegaly.
histopathology:
- name: Megakaryoblast Infiltration
  diagnostic: true
  description: >-
    Blood or marrow contains abnormal blasts with megakaryocytic
    differentiation. Lineage confirmation relies on platelet glycoproteins such
    as CD41, CD61, or CD42b. No current ontology binding is supplied because
    NCIT:C155995 denotes generic myeloblasts rather than megakaryoblasts.
  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: >-
      Blasts express at least one or more of the platelet glycoproteins: CD41
      (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)
    explanation: >-
      WHO defines the lineage by platelet-glycoprotein expression on blasts.
- name: Marrow Reticulin Fibrosis
  finding_term:
    preferred_term: bone marrow fibrosis
    term:
      id: NCIT:C36212
      label: Bone Marrow Fibrosis
  frequency: FREQUENT
  description: >-
    Reticulin fibrosis is variable. The FREQUENT band reflects a 75% rate in one
    prospective pediatric series and should not be read as a universal age- or
    subtype-independent estimate.
  evidence:
  - reference: PMID:12749007
    reference_title: "Biology, clinical, and hematologic features of acute megakaryoblastic leukemia in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow (BM) fibrosis was a constant features in our patients; 75% of
      the patients studied showed this complication at the time of diagnosis.
    explanation: >-
      This supplies a disease-specific pediatric cohort estimate for fibrosis.
phenotypes:
- category: Hematologic
  name: Anemia
  description: >-
    Anemia is documented across adult and infant AMKL series. The finding is
    retained without a universal frequency because the available cohorts are
    small and differently selected.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:23530558
    reference_title: "Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet-derived growth factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All cases had anaemia, but leukocyte and platelet counts varied.
    explanation: >-
      All 18 cases in this clinicopathologic series had anemia.
  - reference: PMID:1510033
    reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients had hepatosplenomegaly and anemia (6 to 8.3 g/dL)
    explanation: >-
      All six infants with t(1;22) AMKL had severe anemia.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Platelet counts are often low, although normal counts can occur. Frequency
    is intentionally omitted because available cohorts do not support one
    universal AMKL-wide category.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:33812402
    reference_title: "[Analysis of Clinical Characteristics and Prognosis in Children with Acute Megakaryoblastic Leukemia without Down Syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the median hemoglobin was 67 g/L and median platelet was 16×109/L.
    explanation: >-
      The reported median platelet count was markedly low in this 19-child
      non-DS cohort.
  - reference: PMID:1510033
    reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four patients had thrombocytopenia (9,000 to 63,000/mm3).
    explanation: >-
      Four of six infants with t(1;22) AMKL were thrombocytopenic.
- category: Hematologic
  name: Myelofibrosis
  description: >-
    Marrow reticulin fibrosis is a characteristic pathologic and clinical
    feature in reported AMKL cohorts.
  phenotype_term:
    preferred_term: Myelofibrosis
    term:
      id: HP:0011974
      label: Myelofibrosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:12749007
    reference_title: "Biology, clinical, and hematologic features of acute megakaryoblastic leukemia in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      75% of the patients studied showed this complication at the time of
      diagnosis.
    explanation: >-
      The frequency band is tied to this prospective pediatric cohort rather
      than generalized to every subtype.
- category: Abdominal
  name: Hepatosplenomegaly
  description: >-
    Liver and spleen enlargement is especially characteristic of infant
    t(1;22) RBM15::MRTFA-rearranged AMKL.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  subtype: RBM15::MRTFA-Rearranged AMKL
  evidence:
  - reference: PMID:1510033
    reference_title: Acute megakaryoblastic leukemia in infants with t(1;22)(p13;q13) abnormality.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All the patients had hepatosplenomegaly and anemia
    explanation: >-
      All six infants in this molecularly defined series had
      hepatosplenomegaly; no categorical prevalence is extrapolated from that
      small cohort.
genetic:
- name: GATA1 Somatic Truncating Mutations
  gene_term:
    preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  association: >-
    GATA1s-generating truncation is a somatic driver in TAM/ML-DS and in a
    distinct pediatric non-DS AMKL subgroup.
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:12172547
    reference_title: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukemic cells from every individual with DS-AMKL that we examined contain
      mutations in GATA1
    explanation: >-
      This establishes the recurrent somatic driver in DS-AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GATA1 mutant calls were absent from these remission samples
    explanation: >-
      Absence from matched remission samples supports a somatic origin in the
      evaluated pediatric non-DS cases.
  - 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: >-
      Myeloid proliferations associated with Down syndrome, typically associated
      with somatic exon 2 or 3 GATA1 mutation ... transient abnormal
      myelopoiesis (TAM) ... and myeloid leukaemia of Down syndrome (ML-DS).
    explanation: >-
      WHO links somatic GATA1 mutation to both TAM and ML-DS.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GATA1 mutant cases comprised a distinct subset at the gene expression level
    explanation: >-
      This supports the distinct pediatric non-DS GATA1-mutant subgroup.
- name: Germline GATA1s-Generating Susceptibility Variants
  gene_term:
    preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  association: >-
    Rare germline GATA1s-generating variants predispose to early-childhood AMKL
    after acquired trisomy 21 or tetrasomy 21.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:34758059
    reference_title: Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on 2 unrelated families that harbor germline GATA1s-generating
      mutations in which several members developed acute megakaryoblastic
      leukemia in early childhood. All evaluable leukemias had acquired trisomy
      21 or tetrasomy 21.
    explanation: >-
      Two families establish a rare germline susceptibility state followed by
      acquired chromosome-21 gain in evaluable leukemias.
- name: RBM15
  gene_term:
    preferred_term: RBM15
    term:
      id: hgnc:14959
      label: RBM15
  association: Somatic driver fusion partner in t(1;22) AMKL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: RBM15::MRTFA-Rearranged AMKL
  evidence:
  - reference: PMID:11431691
    reference_title: "Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show this chromosomal rearrangement to result in the fusion of two novel
      genes, RNA-binding motif protein-15 (RBM15) ... and Megakaryoblastic
      Leukemia-1 (MKL1)
    explanation: >-
      The original report directly identifies RBM15 as one fusion partner.
- name: MRTFA
  gene_term:
    preferred_term: MRTFA
    term:
      id: hgnc:14334
      label: MRTFA
  association: Somatic driver fusion partner, historically named MKL1 or MAL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: RBM15::MRTFA-Rearranged AMKL
  evidence:
  - reference: PMID:11431691
    reference_title: "Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show this chromosomal rearrangement to result in the fusion of two novel
      genes, RNA-binding motif protein-15 (RBM15) ... and Megakaryoblastic
      Leukemia-1 (MKL1)
    explanation: >-
      The original report directly identifies MKL1, now MRTFA, as the second
      fusion partner.
- name: CBFA2T3
  gene_term:
    preferred_term: CBFA2T3
    term:
      id: hgnc:1537
      label: CBFA2T3
  association: Somatic driver fusion partner in cryptic inv(16)
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: CBFA2T3::GLIS2-Positive AMKL
  evidence:
  - reference: PMID:23153540
    reference_title: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis identified a cryptic chromosome 16 inversion
      (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a
      CBFA2T3-GLIS2 fusion protein.
    explanation: >-
      This identifies the cryptic rearrangement and its fusion product.
- name: GLIS2
  gene_term:
    preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  association: Somatic driver fusion partner in cryptic inv(16)
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: CBFA2T3::GLIS2-Positive AMKL
  evidence:
  - reference: PMID:23153540
    reference_title: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data suggest that expression of CBFA2T3-GLIS2 directly contributes
      to leukemogenesis.
    explanation: >-
      Functional models support the fusion's driver role.
- name: NUP98
  gene_term:
    preferred_term: NUP98
    term:
      id: hgnc:8068
      label: NUP98
  association: Somatic driver fusion partner, most commonly with KDM5A in AMKL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: NUP98::KDM5A-Positive AMKL
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent and mutually exclusive chimeric fusion oncogenes have been
      detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene
      rearrangements, most commonly NUP98-KDM5A.
    explanation: >-
      This supports NUP98 rearrangement as a recurrent driver class.
- name: KDM5A
  gene_term:
    preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  association: Somatic driver fusion partner of NUP98
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: NUP98::KDM5A-Positive AMKL
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest
    explanation: >-
      Engineered human-cell models support the fusion's driver effect without
      assigning unsupported retained JmjC demethylase activity.
- name: KMT2A
  gene_term:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  association: Mutually exclusive somatic driver rearrangement in pediatric non-DS AMKL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: KMT2A-Rearranged AMKL
  evidence:
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%.
      These aberrations were mutually exclusive.
    explanation: >-
      This supports KMT2A rearrangement as a recurrent, mutually exclusive
      molecular subgroup.
- name: MPL
  gene_term:
    preferred_term: MPL
    term:
      id: hgnc:7217
      label: MPL
  association: Activating cooperating alteration enriched in HOX-rearranged AMKL
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  subtype: HOX-Rearranged AMKL
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HOXr cases were found to be significantly enriched in activating MPL mutations
    explanation: >-
      This identifies the subgroup-specific cooperating alteration.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When cells were removed from cytokine containing media, however, a growth
      advantage was identified in cells containing both a HOXr and a MPL
      mutation.
    explanation: >-
      A colony-assay growth advantage provides functional, but model-limited,
      support for HOXr/MPL cooperation.
- name: STAG2
  gene_term:
    preferred_term: STAG2
    term:
      id: hgnc:11355
      label: STAG2
  association: >-
    Cooperating cohesin alteration recurrent in DS-ML but not TAM; functional
    cooperation is supported in a trisomy-21/GATA1s iPSC model.
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  subtype: Down Syndrome-Associated AMKL
  evidence:
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      STAG2, a member of the cohesin complex recurrently mutated in DS-ML but not
      in TAM.
    explanation: >-
      This supports association with the DS-ML state, not direct longitudinal
      acquisition during human progression.
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hematopoietic differentiation of GATA1&nbsp;STAG2 double-mutant iPSC lines
      confirmed GATA1s expression and the loss of functional STAG2 protein,
      leading to enhanced production of immature megakaryocytic population
      compared to GATA1 mutant alone.
    explanation: >-
      The engineered iPSC comparison provides functional cooperation evidence
      without proving longitudinal acquisition in human disease.
- name: TET2
  gene_term:
    preferred_term: TET2
    term:
      id: hgnc:25941
      label: TET2
  association: Recurrent adult AMKL genomic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  subtype: Adult AMKL
  evidence: &adult_genomic_evidence
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%),
      PTPN11 (19%) and RUNX1 (15%).
    explanation: >-
      This reports recurrent adult-cohort mutations without proving a
      gene-specific causal route to megakaryoblastic differentiation.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Recurrent adult AMKL genomic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  subtype: Adult AMKL
  evidence: *adult_genomic_evidence
- name: JAK2
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  association: Recurrent adult AMKL genomic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  subtype: Adult AMKL
  evidence: *adult_genomic_evidence
- name: PTPN11
  gene_term:
    preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  association: Recurrent adult AMKL genomic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  subtype: Adult AMKL
  evidence: *adult_genomic_evidence
- name: RUNX1
  gene_term:
    preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  association: Recurrent adult AMKL genomic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  subtype: Adult AMKL
  evidence: *adult_genomic_evidence
progression:
- phase: TAM Precursor State and Resolution
  notes: >-
    In infants with trisomy 21, GATA1-mutant TAM usually resolves over weeks.
    It is a precursor condition rather than an AMKL synonym.
  evidence:
  - reference: PMID:21849481
    reference_title: "Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among those solely observed, peripheral blasts and all other TMD symptoms
      cleared at a median of 36 and 49 days from diagnosis, respectively.
    explanation: >-
      The prospective natural-history study documents spontaneous resolution.
- phase: Progression from TAM to ML-DS
  notes: >-
    A minority of TAM cases later develop ML-DS after acquiring additional
    lesions. Estimates differ with cohort definitions and era: 16% in COG A2971
    and 23% in another prospective series, so no single universal percentage is
    encoded.
  evidence:
  - reference: PMID:21849481
    reference_title: "Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among all, AML subsequently occurred in 16% at a median of 441 days
    explanation: >-
      This gives a cohort-specific prospective progression estimate.
  - reference: PMID:18182574
    reference_title: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 29 (23%) patients with TL subsequently developed ML-DS.
    explanation: >-
      A second cohort demonstrates that progression rates vary by population
      and definition.
- phase: Molecularly Stratified Pediatric Relapse Risk
  subtype: Pediatric Non-Down Syndrome AMKL
  notes: >-
    Pediatric non-DS AMKL outcome is strongly subgroup-dependent.
    CBFA2T3::GLIS2 and KMT2A rearrangements are adverse; GATA1-mutant and HOXr
    subgroups had favorable outcomes in the genomic cohort. These associations
    inform risk stratification but do not establish a universal transplant
    indication.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, CBFA2T3-GLIS2 and KMT2Ar were found to have significantly
      inferior pEFS and pOS.
    explanation: >-
      This supports molecularly stratified adverse outcomes.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GATA1 and HOXr subgroups carried significantly superior outcomes
    explanation: >-
      This supports the favorable-risk contrast in the same cohort.
- phase: Adult Treatment Resistance and Relapse
  notes: >-
    Adult AMKL has low complete-remission rates and short survival. Allogeneic
    transplantation can produce longer survival in selected patients, but
    post-transplant relapse remains frequent.
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete remission rate in 33 patients receiving intensive chemotherapy
      was 33% and median overall survival (OS) was 33 weeks
    explanation: >-
      This quantifies treatment resistance and survival in the adult cohort.
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cumulative incidence of relapse after allo-HSCT was high (62%).
    explanation: >-
      This qualifies transplantation as potentially curative but relapse-prone.
diagnosis:
- name: Bone Marrow Morphology and Blast Assessment
  diagnosis_term:
    preferred_term: biopsy of bone marrow
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  description: >-
    Marrow aspirate and trephine biopsy establish the acute blast process and
    evaluate morphology. For morphology-defined AMKL lacking an AML-defining
    genetic alteration, the shared WHO AML threshold is at least 20% blasts in
    marrow and/or blood, with exclusion of other defined AML and
    mixed-phenotype entities.
  results: >-
    An acute blast process with megakaryoblastic morphology supports AMKL once
    megakaryocytic lineage is confirmed and exclusion criteria are met.
  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: >-
      Shared diagnostic criteria include:
      - ≥20% blasts in bone marrow and/or blood (except for acute erythroid leukaemia).
    explanation: >-
      WHO provides the shared blast criterion for morphology-defined AMKL.
- name: Flow-Cytometric Confirmation of Megakaryocytic Differentiation
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: >-
    Lineage attribution can use flow cytometry and/or immunohistochemistry. With
    flow cytometry, demonstrate at least one platelet glycoprotein on blasts:
    CD41, CD61, or CD42b. A CD42a.CD61-positive/CD13-negative EuroFlow pattern
    is highly specific but only moderately sensitive and cannot be used as the
    sole rule.
  results: >-
    Platelet-glycoprotein expression confirms megakaryocytic differentiation in
    the appropriate acute leukemia context.
  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: >-
      Lineage attribution rests on ... ﬂow cytometry and/or
      immunohistochemistry.
    explanation: >-
      WHO permits lineage attribution by flow cytometry and/or
      immunohistochemistry rather than requiring flow alone.
  - 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: >-
      Blasts express at least one or more of the platelet glycoproteins: CD41
      (glycoprotein llb), CD61 (glycoprotein IIIa), or CD42b (glycoprotein lb)
    explanation: >-
      WHO defines the lineage-confirming markers.
  - reference: PMID:35326734
    reference_title: "Immunophenotypic Analysis of Acute Megakaryoblastic Leukemia: A EuroFlow Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combining CD42a.CD61 (positive) and CD13 (negative) resulted in a
      sensitivity of 71% and a specificity of 99%.
    explanation: >-
      This quantifies a highly specific supportive flow pattern and its
      sensitivity limitation.
- name: Cytogenetic Analysis
  diagnosis_term:
    preferred_term: cytogenetic analysis
    term:
      id: NCIT:C18280
      label: Cytogenetic Analysis
  description: >-
    Tumor karyotyping and targeted FISH detect chromosome-21 abnormalities,
    t(1;22), KMT2A rearrangements, monosomy 7, and other risk lesions, but tumor
    testing alone cannot distinguish constitutional from acquired trisomy 21.
    Matched remission or nonhematopoietic tissue is needed to resolve that
    distinction, especially when mosaicism is possible. Cryptic
    CBFA2T3::GLIS2 and NUP98::KDM5A lesions require targeted FISH, RT-PCR, or
    sequencing rather than conventional karyotyping alone.
  results: >-
    Recurrent cytogenetic and fusion findings assign subtype and inform
    pediatric risk stratification.
  evidence:
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%;
      NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%.
    explanation: >-
      This supports testing for recurrent molecular/cytogenetic risk groups.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3-GLIS2 and NUP98-KDM5A, are missed by conventional karyotyping and
      therefore require split-signal FISH or RT-PCR for detection.
    explanation: >-
      This directly supports targeted testing for the two cryptic fusions.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had non-hematopoietic tissue available for analysis and was
      found to be germline mosaic for trisomy 21
    explanation: >-
      This illustrates why tumor cytogenetics alone cannot exclude constitutional
      mosaic trisomy 21 and why matched nonhematopoietic tissue may be required.
- name: Molecular Testing for GATA1 and Recurrent Fusions
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    In pediatric non-DS AMKL, the cohort-based core recommendation includes
    GATA1, CBFA2T3::GLIS2, KMT2A rearrangements, and NUP98::KDM5A. Broader
    RNA-based fusion profiling can detect additional RBM15::MRTFA and diverse
    HOX-rearranged subgroups. Molecular assignment supports risk stratification
    because major pediatric subgroups differ in outcome and some lesions are
    cryptic.
  results: >-
    Molecular findings classify recurrent non-DS genomic subgroups and, when
    interpreted with constitutional-versus-acquired chromosome-21 status,
    support distinction from ML-DS and risk stratification.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3-GLIS2 and NUP98-KDM5A, are missed by conventional karyotyping and
      therefore require split-signal FISH or RT-PCR for detection.
    explanation: >-
      This directly supports targeted detection of cryptic fusion subgroups.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we recommend all pediatric non-DS-AMKL patients be tested for the presence
      of GATA1 mutations, CBFA2T3-GLIS2, KMT2Ar, and NUP98-KDM5A.
    explanation: >-
      This supports the core molecular test panel.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 93 patients for whom sufficient RNA was available ... 72.4%
      pediatric cases carried a structural variation (SV) predicted to lead to
      a fusion product by RNAseq ... RBM15-MKL1 (10.5%) ... Chimeric transcripts
      not previously described include several fusions involving genes within
      the HOX cluster
    explanation: >-
      The sequencing cohort supports broader RNA-based detection of recurrent
      and diverse fusion subgroups beyond the four-gene core recommendation.
differential_diagnoses:
- name: Transient Abnormal Myelopoiesis
  disease_term:
    preferred_term: transient myeloproliferative syndrome
    term:
      id: MONDO:0008040
      label: transient myeloproliferative syndrome
  description: >-
    Neonatal trisomy-21-associated megakaryoblastic proliferation overlaps most
    directly with Down syndrome-associated AMKL.
  distinguishing_features:
  - Restricted to newborns with trisomy 21 and typically resolves spontaneously.
  - Persistent or later overt leukemia rather than neonatal resolution raises concern for ML-DS.
  evidence:
  - reference: PMID:21849481
    reference_title: "Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transient myeloproliferative disorder (TMD), restricted to newborns with
      trisomy 21, is a megakaryocytic leukemia that although lethal in some is
      distinguished by its spontaneous resolution.
    explanation: >-
      This establishes neonatal restriction and spontaneous resolution.
- name: Acute Panmyelosis with Myelofibrosis
  disease_term:
    preferred_term: acute panmyelosis with myelofibrosis
    term:
      id: MONDO:0019455
      label: acute panmyelosis with myelofibrosis
  description: >-
    A fibrotic acute myeloid neoplasm with substantial morphologic overlap.
  distinguishing_features:
  - >-
    APMF shows trilineage hyperplasia with increased dysplastic megakaryocytes;
    AMKL-MF in the cited cohort showed higher marrow blasts, fewer mature
    megakaryocytes, rare megakaryocytic dysplasia, and chromosome-21 abnormality.
  evidence:
  - reference: PMID:23693053
    reference_title: "Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      APMF showed hyperplasia of all three lineages, increase in megakaryocyte
      count with dysplasia and frequent abnormal karyotypes. AMKL-MF was
      associated with elevated BM blast counts, decreased BM megakaryocyte count
      with rare megakaryocytic dysplasia and chromosome 21 abnormality.
    explanation: >-
      This directly compares two fibrotic acute myeloid presentations and
      refutes use of increased mature megakaryocytes as a general AMKL phenotype.
- name: Primary Myelofibrosis
  disease_term:
    preferred_term: primary myelofibrosis
    term:
      id: MONDO:0009692
      label: primary myelofibrosis
  description: >-
    A chronic myeloproliferative neoplasm that can overlap through fibrosis and
    splenomegaly.
  distinguishing_features:
  - >-
    Rare peripheral/marrow blasts and JAK2 V617F favored PMF in the comparative
    cohort; AMKL requires an acute blast process with megakaryocytic-lineage
    markers.
  evidence:
  - reference: PMID:23693053
    reference_title: "Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PMF patients displayed splenomegaly, rare blasts in PB/BM, and JAK2 V617F
      mutation.
    explanation: >-
      This identifies distinguishing features in the comparison cohort.
- name: Myelodysplastic Syndrome with Myelofibrosis
  description: >-
    A fibrotic myelodysplastic presentation with cytopenias and trilineage
    dysplasia that can mimic AMKL with fibrosis. No exact MONDO binding is
    supplied for this composite label.
  distinguishing_features:
  - >-
    Pancytopenia, trilineage dysplasia, and recurrent chromosome 5, 7, 12, or 17
    abnormalities favored MDS-MF in the cited cohort.
  evidence:
  - reference: PMID:23693053
    reference_title: "Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MDS-MF patients showed pancytopenia, dysplasia in all three lineages and
      recurrent chromosomal abnormalities involving chromosome 5,7,12, and 17.
    explanation: >-
      This defines distinguishing cohort features.
- name: Megakaryocytic Blast Phase of Chronic Myeloid Leukemia
  description: >-
    CML blast phase can acquire a megakaryocytic phenotype and share platelet
    glycoprotein expression with de novo AMKL.
  distinguishing_features:
  - >-
    Establish prior or concurrent CML/BCR::ABL1 context; the comparative adult
    series found more myeloperoxidase-positive blasts in megakaryocytic CML blast
    phase and more CD15 expression in de novo AMKL.
  evidence:
  - reference: PMID:14968469
    reference_title: "[Survival, clinical and laboratory characteristics of de novo and secondary megakaryoblastic leukemia]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Leukemic cells of patients with AMegL expressed more frequently CD15
      antigen than blast cells of those with MegBC-CML (83% and 37.5%; p < 0.05).
      In contrast, blast cells expressing myeloperoxidase were present in 50% and
      10% of cases with MegBC-CML and AMegL, respectively
    explanation: >-
      Direct comparison documents immunophenotypic differences while reinforcing
      the need to establish the underlying CML context.
- name: T-Lymphoblastic or Mixed-Lineage Acute Leukemia
  description: >-
    CBFA2T3::GLIS2-positive acute leukemia can coexpress T-lineage and
    megakaryocytic markers, creating a lineage-assignment pitfall.
  distinguishing_features:
  - >-
    Bright CD56 with dim or negative HLA-DR, CD38, and CD45 (the RAM phenotype),
    megakaryocytic markers, and direct detection of CBFA2T3::GLIS2 support the
    fusion-positive AML spectrum.
  evidence:
  - reference: PMID:37601875
    reference_title: "CBFA2T3::GLIS2-positive acute leukemia with RAM and mixed T/megakaryocytic phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3::GLIS2-positive acute leukemia with T/megakaryocytic markers could
      be misdiagnosed as T-lymphoblastic leukemia/lymphoma, early T-cell
      precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia,
      AML with minimal differentiation, or AML with myelodysplasia-related changes.
    explanation: >-
      This directly identifies the diagnostic pitfall and its competing
      classifications.
treatments:
- name: Reduced-Intensity Cytarabine-Based Chemotherapy for ML-DS
  action_category: THERAPEUTIC
  role: First-line
  context: Children with ML-DS; evidence is not stratified by megakaryoblastic morphology
  description: >-
    Children with ML-DS are treated with reduced-intensity AML regimens tailored
    to their high cytotoxic-drug susceptibility. In ML-DS 2006, reducing
    cumulative etoposide, reducing intrathecal prophylaxis, and omitting
    maintenance preserved excellent survival relative to the historical
    reduced-intensity control. This evidence supports a specific tested regimen,
    not arbitrary further deintensification, and applies to the ML-DS trial
    population rather than a morphology-stratified DS-AMKL subset.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
    - preferred_term: etoposide
      term:
        id: CHEBI:4911
        label: etoposide
  target_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    treatment_effect: INHIBITS
    description: >-
      Cytotoxic therapy reduces leukemic cell burden; it does not reverse
      trisomy 21 or the GATA1 mutation.
    evidence:
    - reference: PMID:28400376
      reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64),
        event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and
        cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%;
        PGray = .03) did not significantly differ
      explanation: >-
        Clinical outcomes indirectly support control of leukemic burden; this
        does not establish reversal of the underlying differentiation program.
  evidence:
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with myeloid leukemia associated with Down syndrome (ML-DS) have
      superior outcome compared with non-DS patients, but suffer from higher
      constitutional cytotoxic drug susceptibility.
    explanation: >-
      This directly supports tailoring intensity to the heightened cytotoxic
      drug susceptibility of children with ML-DS.
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intensity-reduced induction and reinduction therapy with cytarabine and
      idarubicin with or without etoposide was replaced with CPX-351
    explanation: >-
      ML-DS 2018 identifies the intensity-reduced predecessor backbone as
      cytarabine-based; it does not define the complete ML-DS 2006 regimen.
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment intensity was reduced by lowering the cumulative dose of
      etoposide (950 to 450 mg/m2) and intrathecal central nervous system
      prophylaxis while omitting maintenance therapy.
    explanation: >-
      This states the actual deintensification tested in ML-DS 2006.
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64),
      event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and
      cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%;
      PGray = .03) did not significantly differ
    explanation: >-
      The tested reductions preserved excellent survival and relapse outcomes.
- name: Intensive Pediatric AML Chemotherapy for Non-DS AMKL
  action_category: THERAPEUTIC
  role: First-line
  context: Pediatric Non-Down Syndrome AMKL
  description: >-
    Pediatric non-DS AMKL is treated with intensive multi-agent AML therapy.
    Survival improved substantially between AML-BFM 98 and AML-BFM 04, but
    molecular subgroup and early response remain important risk variables.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  target_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    treatment_effect: INHIBITS
    description: >-
      Intensive AML chemotherapy reduces leukemic cell burden; this is not a
      fusion-specific targeted effect or evidence of restored maturation.
    evidence:
    - reference: PMID:25913479
      reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98
        (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041).
      explanation: >-
        Improved survival indirectly supports disease-burden control but does
        not establish a fusion-specific or differentiation-restoring mechanism.
  evidence:
  - reference: PMID:25913479
    reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98
      (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041).
    explanation: >-
      The prospective multicenter studies document improved survival in the
      later intensive-treatment era.
  - reference: PMID:25913479
    reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, with intensive therapy regimens, a steep increase in the
      survival rates was achieved.
    explanation: >-
      This supports intensive AML therapy as the pediatric non-DS treatment
      backbone.
  - reference: PMID:25913479
    reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      multivariate analysis showed that treatment response (bone marrow
      morphology on day 15 and 28) was the only independent prognostic marker
    explanation: >-
      This directly supports early morphologic response as a risk variable in
      the AML-BFM cohorts.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pediatric non-DS-AMKL is a heterogeneous malignancy comprised of distinct
      subsets as defined by next generation sequencing with varying outcomes.
    explanation: >-
      This directly supports molecular subgroup as an outcome-associated risk
      variable.
- name: Allogeneic Hematopoietic Cell Transplantation for Selected Pediatric Non-DS AMKL
  therapeutic_modality: CELL_THERAPY
  action_category: THERAPEUTIC
  role: Risk-adapted consolidation or salvage
  context: >-
    Selected high-risk pediatric non-DS AMKL in remission; benefit in first
    complete remission remains uncertain
  description: >-
    Allogeneic HCT may be considered for selected high-risk or poorly responding
    non-DS AMKL, but it is not a uniformly established CR1 standard.
    Comparative cohorts have not established a net CR1 survival benefit, while
    registry data among transplanted patients show better outcomes in CR1 than
    later or outside remission.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    treatment_effect: INHIBITS
    description: >-
      Conditioning and graft-mediated antileukemic effects aim to eradicate the
      leukemic clone and restore donor hematopoiesis.
    evidence:
    - reference: PMID:36786154
      reference_title: Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The 5-year OS rate was significantly higher for patients who underwent
        HCT in the first complete remission (CR1, 72%) than for those in the
        second CR (CR2, 23%) and non-CR (16%)
      explanation: >-
        Outcomes by remission state indirectly support antileukemic disease
        control, without identifying a specific differentiation mechanism.
  evidence:
  - reference: PMID:25913479
    reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic hematopoietic stem cell transplantation in first remission did
      not provide a significant survival benefit
    explanation: >-
      This argues against encoding transplant as universally beneficial in CR1.
  - reference: PMID:36786154
    reference_title: Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 5-year OS rate was significantly higher for patients who underwent HCT
      in the first complete remission (CR1, 72%) than for those in the second CR
      (CR2, 23%) and non-CR (16%)
    explanation: >-
      Among transplanted patients, remission state strongly affected outcome;
      the registry lacks a chemotherapy-only comparator.
  - reference: PMID:41228304
    reference_title: "Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia Patients Have Dismal Outcomes Irrespective of Allogeneic Hematopoietic Stem Cell Transplant: A Single-Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with allo-HSCT did not improve outcomes due to the high CIR, even
      after HSCT in CR1.
    explanation: >-
      A recent small cohort reinforces uncertainty about a CR1 survival benefit.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore patients carrying CBFA2T3-GLIS2 or KMT2Ar that have inferior
      outcomes may benefit from allogeneic SCT in first complete remission.
      While NUP98-KDM5A outcomes did not reach statistical significance, their
      pEFS and pOS warrant close monitoring and consideration of allogeneic SCT
      as well.
    explanation: >-
      This is the retrospective study authors' risk-adapted proposal, not a
      demonstrated transplant benefit or a prospective recommendation.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transplant in first remission should be reserved for those showing a poor
      response to induction therapy (e.g. high levels of minimal residual disease).
    explanation: >-
      This is the retrospective authors' proposal for poorly responding cases,
      not evidence that transplant improves survival in that group.
- name: Intensive Chemotherapy for Fit Adults
  action_category: THERAPEUTIC
  role: Remission induction
  context: Adult AMKL
  description: >-
    Fit adults may receive intensive AML chemotherapy, but dedicated AMKL data
    show low complete-remission rates and very short survival. This is a
    treatment option with limited effectiveness rather than a favorable
    evidence-based expectation.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  target_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    treatment_effect: INHIBITS
    description: Intensive chemotherapy aims to reduce adult AMKL leukemic-cell burden.
    evidence:
    - reference: PMID:37455345
      reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complete remission rate in 33 patients receiving intensive chemotherapy
        was 33% and median overall survival (OS) was 33 weeks
      explanation: >-
        The remission rate indirectly supports blast-burden reduction while the
        poor survival documents limited effectiveness.
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete remission rate in 33 patients receiving intensive chemotherapy
      was 33% and median overall survival (OS) was 33 weeks
    explanation: >-
      This supports use of intensive therapy in the cohort while documenting
      its limited effectiveness.
- name: Allogeneic Hematopoietic Cell Transplantation for Eligible Adults
  therapeutic_modality: CELL_THERAPY
  action_category: THERAPEUTIC
  role: Potentially curative consolidation or salvage
  context: Adult AMKL achieving sufficient disease control
  description: >-
    Adult cohort data describe allogeneic HSCT as the only potentially curative
    option, but selection bias is unavoidable and post-transplant relapse
    remains high.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    treatment_effect: INHIBITS
    description: >-
      Transplant conditioning and graft-mediated effects aim to eliminate the
      resistant adult AMKL clone.
    evidence:
    - reference: PMID:37455345
      reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks;
        95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50),
        although cumulative incidence of relapse after allo-HSCT was high (62%).
      explanation: >-
        These outcomes indirectly support antileukemic disease control while
        documenting substantial post-transplant relapse.
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far allo-HSCT is the only potentially curative treatment option in this
      dismal AML subgroup.
    explanation: >-
      This is the adult cohort authors' interpretation and is retained with
      partial support because the observational design cannot prove uniqueness.
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks;
      95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50),
      although cumulative incidence of relapse after allo-HSCT was high (62%).
    explanation: >-
      This supports potential benefit while explicitly documenting high relapse.
- name: GATA1 Measurable Residual Disease Monitoring in ML-DS
  action_category: MONITORING
  role: Response and relapse-risk monitoring
  context: ML-DS treated in the ML-DS 2018 trial
  description: >-
    Error-corrected next-generation sequencing of the leukemia-associated GATA1
    mutation can monitor molecular residual disease in ML-DS. In ML-DS 2018,
    positivity was associated with increased relapse risk; this evidence does
    not establish generic flow-cytometric or fusion-based MRD monitoring for all
    AMKL subtypes.
  evidence:
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Positive MRD by error-corrected GATA1 next-generation sequencing, the
      presence of trisomy 8 or a complex karyotype were associated with an
      increased risk for relapse.
    explanation: >-
      This supports error-corrected GATA1 molecular MRD as a relapse-risk
      monitoring tool in the ML-DS 2018 population.
clinical_trials:
- name: ML-DS 2006 (EudraCT 2007-006219-2)
  description: >-
    Prospective multicenter, open-label, nonrandomized treatment-reduction study
    in 170 children with ML-DS. Published final results support lowering
    etoposide and intrathecal prophylaxis and omitting maintenance without
    impairing excellent outcome. The publication reports ML-DS as a whole and
    does not provide morphology-stratified DS-AMKL trial results.
  evidence:
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in
      the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial
    explanation: >-
      This defines the design and population of the published trial.
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study reveals prognostic markers for children with ML-DS and
      illustrates that reducing therapy did not impair excellent outcome.
    explanation: >-
      This directly supports the trial-level conclusion that the tested
      reductions preserved outcome.
- name: ML-DS 2018 (EudraCT 2018-002988-25)
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Phase III study replacing intensity-reduced induction/reinduction with
    CPX-351 in ML-DS. It was halted after 35 enrollments because relapse was
    unexpectedly high. Toxicity was favorable, but 24-month EFS was inferior to
    the historical ML-DS 2006 result, so CPX-351 substitution is not encoded as
    recommended therapy. Results are ML-DS-wide rather than stratified by
    megakaryoblastic morphology.
  evidence:
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 35 patients were enrolled until the trial was halted because of
      an unexpectedly high relapse rate.
    explanation: >-
      This documents enrollment and early termination.
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A per-protocol interim analysis revealed a significantly lower 24-month
      EFS when compared with the ML-DS 2006 trial (69% vs 90%; P< .001).
    explanation: >-
      The negative efficacy result prevents treatment recommendation despite
      favorable toxicity.
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CPX-351 demonstrated a favorable toxicity profile with no treatment-related
      mortality.
    explanation: >-
      This directly supports the favorable-toxicity qualification while the EFS
      result remains unfavorable.
animal_models:
- species: mouse
  genotype: Ott-Mal knock-in donor marrow retrovirally transduced ex vivo with MPLW515L and transplanted into lethally irradiated WT C57BL/6 recipients
  background: C57BL/6
  category: Transduction/transplant cooperation model
  genes:
  - preferred_term: RBM15
    term:
      id: hgnc:14959
      label: RBM15
  - preferred_term: MRTFA
    term:
      id: hgnc:14334
      label: MRTFA
  - preferred_term: MPL
    term:
      id: hgnc:7217
      label: MPL
  description: >-
    Primary marrow from nonleukemic Ott-Mal knock-in donors is transduced ex
    vivo with MPLW515L and transplanted into lethally irradiated wild-type
    recipients. This is a two-hit transduction/transplant cooperation model,
    not a mouse carrying an inherited activating Mpl allele.
  associated_phenotypes:
  - Megakaryoblast hyperproliferation and maturation block
  - Thrombocytopenia
  - Organomegaly
  - Extensive fibrosis
  evidence:
  - reference: PMID:19287095
    reference_title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      BM cells from 2-month-old nonleukemic OM or WT littermates ...
      retroviruses harboring the MPL W515L allele ... lethally irradiated WT
      C57BL/6 recipients
    explanation: >-
      This directly identifies the ex-vivo transduction and recipient-transplant
      construction of the cooperation model.
  - reference: PMID:19287095
    reference_title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cooperation between OTT-MAL and an activating mutation of the
      thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL)
      efficiently induced a short-latency AMKL that recapitulated all the
      features of human AMKL, including megakaryoblast hyperproliferation and
      maturation block, thrombocytopenia, organomegaly, and extensive fibrosis.
    explanation: >-
      This supports the associated model phenotypes while retaining the
      requirement for forced MPL cooperation.
- species: mouse
  genotype: Human pediatric AMKL patient-cell xenotransplant
  background: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG)
  category: Patient-derived xenograft
  description: >-
    Patient-derived pediatric non-DS AMKL xenografts reproduce human leukemic
    growth and provide an in-vivo platform for molecular discovery and
    preclinical drug screening.
  evidence:
  - reference: PMID:23045605
    reference_title: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, we show that AMKL xenograft models constitute a relevant in vivo
      preclinical screening platform to validate the efficacy of novel therapies
      such as Aurora A kinase inhibitors.
    explanation: >-
      This establishes the patient-derived xenograft as a screening platform,
      not a clinical treatment recommendation.
- species: mouse
  genotype: NUP98-KDM5A-transduced human cord-blood HSPC xenograft
  background: immunodeficient
  category: Synthetic human xenograft model
  genes:
  - preferred_term: NUP98
    term:
      id: hgnc:8068
      label: NUP98
  - preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  description: >-
    Synthetic NUP98::KDM5A human-cell xenografts can generate AMKL-like disease
    and expose preclinical signaling vulnerabilities.
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient
      mice led to multiple subtypes of leukemia, including AMKL, that phenocopy
      human disease phenotypically and molecularly.
    explanation: >-
      The synthetic xenograft phenocopies human NUP98::KDM5A AMKL.
- species: mouse
  genotype: CBFA2T3-GLIS2-transduced human cord-blood HSPC xenograft
  background: NSG-SGM3
  category: Synthetic human xenograft model
  genes:
  - preferred_term: CBFA2T3
    term:
      id: hgnc:1537
      label: CBFA2T3
  - preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  description: >-
    Fusion-transduced human cord-blood progenitors generate aggressive
    CBFA2T3::GLIS2-positive leukemia in xenografts and support preclinical
    target evaluation.
  evidence:
  - reference: PMID:36136600
    reference_title: CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the expression of the C/G oncogenic fusion protein promotes the
      transformation of human cord blood hematopoietic stem and progenitor cells
      (CB HSPCs) in an endothelial cell coculture system that recapitulates the
      transcriptome, morphology, and immunophenotype of C/G acute myeloid
      leukemia (AML) and induces highly aggressive leukemia in xenograft models.
    explanation: >-
      The engineered human cells induce aggressive fusion-positive leukemia in
      vivo.
experimental_models:
- name: Trisomy-21 GATA1/STAG2 Double-Mutant iPSC Model
  description: >-
    Hematopoietic differentiation of gene-targeted trisomy-21 iPSCs models a
    progression-like, DS-ML-like immature megakaryocytic phenotype in vitro; it
    does not demonstrate overt AMKL in a patient or animal.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  conditions:
  - TAM/ML-DS progression model
  - trisomy 21
  - GATA1 mutation
  - STAG2 knockout
  cell_source: >-
    Trisomy-21 induced pluripotent stem cells with engineered GATA1 and STAG2
    mutations
  culture_system: Hematopoietic differentiation and megakaryocyte-lineage expansion
  publication: PMID:35203280
  modeled_mechanisms:
  - target: Trisomy 21 and GATA1 Truncation Generate GATA1s
    description: Recapitulates GATA1s production in trisomy-21 hematopoietic progenitors.
    evidence:
    - reference: PMID:35203280
      reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We previously developed a model for TAM by introducing disease-specific
        GATA1 mutation in trisomy 21-induced pluripotent stem cells (iPSCs),
        leading to the production of N-terminally truncated short form of GATA1
        (GATA1s).
      explanation: >-
        This directly supports the model link to trisomy-21-associated GATA1s
        production.
  - target: STAG2 Loss Enhances Immature Megakaryopoiesis in a Trisomy-21/GATA1s iPSC Model
    description: Models the incremental effect of engineered STAG2 loss beyond GATA1 mutation alone.
    evidence:
    - reference: PMID:35203280
      reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this model, we used CRISPR/Cas9 to introduce a co-operating mutation
        in STAG2, a member of the cohesin complex recurrently mutated in DS-ML
        but not in TAM.
      explanation: >-
        This directly identifies the engineered cooperating lesion in the iPSC
        system.
  - target: Immature Megakaryocytic Leukemic State
    description: Measures enhanced production of an immature megakaryocytic population in vitro.
    evidence:
    - reference: PMID:35203280
      reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Hematopoietic differentiation of GATA1&nbsp;STAG2 double-mutant iPSC
        lines confirmed GATA1s expression and the loss of functional STAG2
        protein, leading to enhanced production of immature megakaryocytic
        population compared to GATA1 mutant alone.
      explanation: >-
        This directly supports the immature-megakaryocytic-state readout.
  findings:
  - statement: Megakaryocyte-specific lineage expansion of the double-mutant HSPCs resembled the DS-ML immunophenotype.
    supporting_text: >-
      Megakaryocyte-specific lineage expansion of the double-mutant HSPCs
      exhibited close resemblance to the DS-ML immunophenotype.
    evidence:
    - reference: PMID:35203280
      reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Megakaryocyte-specific lineage expansion of the double-mutant HSPCs
        exhibited close resemblance to the DS-ML immunophenotype.
      explanation: >-
        This is the source's direct phenotypic characterization of the
        double-mutant lineage-expansion experiment.
  evidence:
  - reference: PMID:35203280
    reference_title: Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In conclusion, we developed a DS-ML model via hematopoietic differentiation
      of gene-targeted iPSCs bearing trisomy 21.
    explanation: >-
      The publication explicitly identifies the engineered iPSC system as a
      DS-ML model.
- name: NUP98-KDM5A Cord-Blood HSPC Model
  description: >-
    Lentiviral NUP98::KDM5A expression in human cord-blood HSPCs creates a
    synthetic model of fusion-driven maturation arrest and progenitor
    persistence.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  conditions:
  - NUP98::KDM5A-Positive AMKL
  - NUP98-KDM5A expression
  - maturation arrest
  cell_source: Human cord-blood hematopoietic stem and progenitor cells
  culture_system: Lentiviral transduction in optimized hematopoietic culture
  publication: PMID:31698461
  modeled_mechanisms:
  - target: NUP98::KDM5A Sustains Progenitor Capacity and Maturation Arrest
    description: Models the fusion-driven leukemic state.
    evidence:
    - reference: PMID:31698461
      reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The NUP98-KDM5A fusion oncogene was a potent inducer of maturation
        arrest, sustaining long-term proliferative and progenitor capacities of
        engineered cells in optimized culture conditions.
      explanation: >-
        This directly supports the fusion-specific model link.
  - target: Immature Megakaryocytic Leukemic State
    description: Recapitulates maturation arrest and sustained progenitor capacity.
    evidence:
    - reference: PMID:31698461
      reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The NUP98-KDM5A fusion oncogene was a potent inducer of maturation
        arrest, sustaining long-term proliferative and progenitor capacities of
        engineered cells in optimized culture conditions.
      explanation: >-
        The engineered-cell result directly supports the model's immature-state
        readout.
  findings:
  - statement: NUP98::KDM5A induced maturation arrest and long-term progenitor capacity.
    supporting_text: >-
      The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest,
      sustaining long-term proliferative and progenitor capacities of engineered
      cells in optimized culture conditions.
    evidence:
    - reference: PMID:31698461
      reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The NUP98-KDM5A fusion oncogene was a potent inducer of maturation
        arrest, sustaining long-term proliferative and progenitor capacities of
        engineered cells in optimized culture conditions.
      explanation: >-
        This is the source's direct in-vitro finding for the engineered HSPCs.
  evidence:
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and
      progenitor cells using a lentiviral-based approach to create
      physiopathologically relevant disease models.
    explanation: >-
      This directly describes the engineered human-cell model.
- name: CBFA2T3-GLIS2 Cord-Blood HSPC Endothelial Coculture
  description: >-
    Fusion-transduced human cord-blood HSPCs maintained with endothelial cells
    recapitulate fusion-positive AML transcriptional, morphologic, and
    immunophenotypic features.
  experimental_model_type: CO_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  conditions:
  - CBFA2T3::GLIS2-Positive AMKL
  - CBFA2T3-GLIS2 expression
  - endothelial niche
  cell_source: >-
    Human cord-blood hematopoietic stem and progenitor cells plus endothelial
    cells
  culture_system: Endothelial cell coculture
  publication: PMID:36136600
  modeled_mechanisms:
  - target: Immature Megakaryocytic Leukemic State
    description: Recapitulates fusion-positive AML morphology and immunophenotype.
    evidence:
    - reference: PMID:36136600
      reference_title: CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the expression of the C/G oncogenic fusion protein promotes the
        transformation of human cord blood hematopoietic stem and progenitor
        cells (CB HSPCs) in an endothelial cell coculture system that
        recapitulates the transcriptome, morphology, and immunophenotype of C/G
        acute myeloid leukemia (AML)
      explanation: >-
        This directly supports the coculture's fusion-positive cellular-state
        readout without importing BMP results from a different model.
  findings:
  - statement: The endothelial niche supports transformation of fusion-transduced cord-blood HSPCs.
    supporting_text: >-
      the expression of the C/G oncogenic fusion protein promotes the
      transformation of human cord blood hematopoietic stem and progenitor cells
      (CB HSPCs) in an endothelial cell coculture system that recapitulates the
      transcriptome, morphology, and immunophenotype of C/G acute myeloid
      leukemia (AML)
    evidence:
    - reference: PMID:36136600
      reference_title: CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the expression of the C/G oncogenic fusion protein promotes the
        transformation of human cord blood hematopoietic stem and progenitor
        cells (CB HSPCs) in an endothelial cell coculture system that
        recapitulates the transcriptome, morphology, and immunophenotype of C/G
        acute myeloid leukemia (AML)
      explanation: >-
        This is the directly reported coculture transformation finding.
  evidence:
  - reference: PMID:36136600
    reference_title: CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the expression of the C/G oncogenic fusion protein promotes the
      transformation of human cord blood hematopoietic stem and progenitor cells
      (CB HSPCs) in an endothelial cell coculture system that recapitulates the
      transcriptome, morphology, and immunophenotype of C/G acute myeloid
      leukemia (AML)
    explanation: >-
      This directly describes the human endothelial-coculture model.
discussions:
- discussion_id: controversy_amkl_hct_cr1_benefit
  prompt: >-
    Which molecular-risk groups of pediatric non-DS AMKL derive a net survival
    benefit from allogeneic HCT in first complete remission rather than
    chemotherapy alone?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - treatments#Allogeneic Hematopoietic Cell Transplantation for Selected Pediatric Non-DS AMKL
  - has_subtypes#CBFA2T3::GLIS2-Positive AMKL
  - has_subtypes#NUP98::KDM5A-Positive AMKL
  rationale: >-
    Retrospective series disagree and are vulnerable to selection, response,
    molecular-composition, and treatment-era effects. The entry therefore
    encodes HCT as risk-adapted and uncertain rather than uniformly beneficial.
  evidence:
  - reference: PMID:25913479
    reference_title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic hematopoietic stem cell transplantation in first remission did
      not provide a significant survival benefit
    explanation: >-
      One large pediatric cohort found no significant CR1 survival advantage.
  - reference: PMID:36786154
    reference_title: Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Risk stratification in patients with non-DS-AMKL should be established to
      determine HCT indication in CR1.
    explanation: >-
      Registry investigators explicitly leave CR1 indication unresolved.
  - reference: PMID:41228304
    reference_title: "Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia Patients Have Dismal Outcomes Irrespective of Allogeneic Hematopoietic Stem Cell Transplant: A Single-Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with allo-HSCT did not improve outcomes due to the high CIR, even
      after HSCT in CR1.
    explanation: >-
      A recent single-center comparison reinforces the uncertainty.
- discussion_id: gap_ml_ds_dose_intensity
  prompt: >-
    What induction formulation and dose intensity preserves ML-DS event-free
    survival while minimizing treatment-related toxicity?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Reduced-Intensity Cytarabine-Based Chemotherapy for ML-DS
  - has_subtypes#Down Syndrome-Associated AMKL
  rationale: >-
    ML-DS 2006 preserved outcome after selected reductions, whereas replacing
    induction with CPX-351 in ML-DS 2018 reduced EFS despite favorable toxicity.
  evidence:
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study reveals prognostic markers for children with ML-DS and
      illustrates that reducing therapy did not impair excellent outcome.
    explanation: >-
      Selected reductions preserved outcomes in ML-DS 2006.
  - reference: PMID:41118594
    reference_title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      replacing intensity-reduced induction therapy with CPX-351 in ML-DS led to
      a significantly lower EFS, highlighting the need for dose optimization to
      balance the efficacy and toxicity
    explanation: >-
      A different substitution strategy failed to preserve EFS.
- discussion_id: interpretation_rbm15_mrtfa_mpl_model
  prompt: >-
    How much of human RBM15::MRTFA AMKL is faithfully modeled by the Ott-Mal
    donor-marrow/MPLW515L transduction-transplant system used to produce
    short-latency leukemia?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#RBM15::MRTFA Fusion Deregulates RBPJ Transcription
  - animal_models#Ott-Mal knock-in donor marrow retrovirally transduced ex vivo with MPLW515L and transplanted into lethally irradiated WT C57BL/6 recipients
  rationale: >-
    The model demonstrates functional cooperation and reproduces many human
    features, but it may overrepresent MPL-dependent biology.
  proposed_experiments:
  - experiment_id: exp_amkl_rbm15_mrtfa_mpl_dependency
    name: RBM15::MRTFA dependence on forced MPL signaling across matched human and mouse models
    description: >-
      Profile MPL-pathway lesions and signaling in human RBM15::MRTFA-positive
      AMKL, then compare Ott-Mal knock-in donor marrow transplanted after
      matched no-vector, MPL-WT, and MPLW515L transduction. Measure leukemia
      latency, lineage state, fibrosis, and transcriptional similarity to the
      human tumors.
    decision_criterion: >-
      Determine whether fusion-positive human tumors share the MPL-dependent
      state required for short-latency leukemia in the mouse transplant model.
  evidence:
  - reference: PMID:19287095
    reference_title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cooperation between OTT-MAL and an activating mutation of the
      thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL)
      efficiently induced a short-latency AMKL
    explanation: >-
      This is both the model's mechanistic strength and the reason to qualify
      extrapolation to every human fusion-positive case.
- discussion_id: gap_adult_amkl_causal_biology
  prompt: >-
    Which recurrent adult AMKL genomic lesions directly specify
    megakaryoblastic differentiation and which primarily mark adverse-risk
    clonal myeloid disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Adult Adverse Genomic Landscape and Therapy Resistance
  - has_subtypes#Adult AMKL
  rationale: >-
    Adult cohorts define recurrent mutations and dismal outcomes, but do not
    resolve a causal differentiation program comparable with pediatric fusion
    subgroups.
  evidence:
  - reference: PMID:37455345
    reference_title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%),
      PTPN11 (19%) and RUNX1 (15%).
    explanation: >-
      The cohort defines the association set but not lesion-specific
      differentiation mechanisms.
- discussion_id: gap_preclinical_target_translation
  prompt: >-
    Which preclinical AMKL targets can produce safe and durable clinical benefit
    across or within molecular subgroups?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - experimental_models#NUP98-KDM5A Cord-Blood HSPC Model
  - experimental_models#CBFA2T3-GLIS2 Cord-Blood HSPC Endothelial Coculture
  rationale: >-
    Aurora A inhibition, JAK inhibition, CD56-directed therapy, and FOLR1 CAR T
    cells have promising model evidence, but none is encoded as established AMKL
    treatment. On-target FOLR1 expression in normal kidney and lung raises a
    specific safety concern.
  evidence:
  - reference: PMID:36136600
    reference_title: CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns
      for toxicity that must be addressed for the clinical application of this
      therapy.
    explanation: >-
      This directly identifies the translational safety barrier for the
      preclinical FOLR1 strategy.
  - reference: PMID:31698461
    reference_title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both synthetic models and patient-derived xenografts of NUP98-rearranged
      AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically
      approved JAK2 inhibitor.
    explanation: >-
      This is preclinical vulnerability evidence, not an AMKL clinical efficacy
      result.
references:
- reference: PMID:35732831
  title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
  findings: []
- reference: PMID:12172547
  title: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
  findings: []
- reference: PMID:28112737
  title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
  findings: []
- reference: PMID:37455345
  title: Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
  findings: []
- reference: PMID:19287095
  title: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
  findings: []
- reference: PMID:23153540
  title: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
  findings: []
- reference: PMID:31698461
  title: Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.
  findings: []
- reference: PMID:28400376
  title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
  findings: []
- reference: PMID:25913479
  title: Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.
  findings: []
- reference: PMID:41118594
  title: "CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial."
  findings: []
notes: >-
  The earlier fallback research artifact records provider failures and manual
  fallback notes rather than a completed deep-research report. This review was
  rebuilt from fetched source records and independently audited for science,
  ontology/schema structure, exact evidence support, clinical trials, and model
  systems. Diagnostic assay entries formerly placed under biochemical were
  moved to diagnosis; TAM therapy was removed from root AMKL treatments because
  TAM is a distinct precursor condition.
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
datasets:
- accession: ega:EGAS00001002183
  title: Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia is Characterized by Distinct Genomic Subsets with Varying Outcomes
  description: Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While extremely rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML1-3. A significant proportion of pediatric AMKL cases occur in children with Down syndrome (DS). These patients have excellent outcomes and are characterized at the genomic level by a founding GATA1 mutation4-6. In contrast, AMKL in patients without DS (non-DS-AMKL) is frequently associated with poor outcomes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Acute Megakaryoblastic Leukemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000612
  title: Single cell transcriptome analysis of pediatric acute megakaryoblastic leukemia
  description: Pediatric acute megakaryoblastic leukemia presenting fusion oncogene is generally associated with a poor prognosis. We performed single transcriptome analyses on bone marrow samples from pediatric acute megakaryoblastic leukemia patients presenting the ETO2-GLIS2 fusion oncogene.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Acute Megakaryoblastic Leukemia"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

📚

References & Deep Research

References

10

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:12172547

Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.

No top-level findings curated for this source.

PMID:28112737

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.

No top-level findings curated for this source.

PMID:37455345

Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.

No top-level findings curated for this source.

PMID:19287095

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.

No top-level findings curated for this source.

PMID:23153540

An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.

No top-level findings curated for this source.

PMID:31698461

Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.

No top-level findings curated for this source.

PMID:28400376

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial.

No top-level findings curated for this source.

PMID:25913479

Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.

No top-level findings curated for this source.

PMID:41118594

CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial.

No top-level findings curated for this source.

Deep Research

1

Acute Megakaryoblastic Leukemia Deep Research Fallback ▸

Acute Megakaryoblastic Leukemia Deep Research Fallback

Provider Attempts

2026-05-08T18:00Z: just research-disorder asta Acute_Megakaryoblastic_Leukemia failed because ASTA_API_KEY was not set; the runner reported ERROR - No research providers available. Please set API keys.
2026-05-08T18:00Z: just research-disorder openai Acute_Megakaryoblastic_Leukemia failed for the same reason (no OPENAI_API_KEY).
2026-05-08T18:00Z: just research-disorder perplexity Acute_Megakaryoblastic_Leukemia failed for the same reason (no PERPLEXITY_API_KEY).
2026-05-08T18:00Z: just research-disorder falcon Acute_Megakaryoblastic_Leukemia failed for the same reason (no Edison/Falcon API key, and agentapi is not available in PATH on the worktree host).

No provider-generated research artifact was available. Curation therefore proceeded from cached PubMed references already pinned to this disorder, with no hand-edited references_cache/*.md files.

Evidence Scope Used For Curation

PMID:8069184 — Phenotypic characteristics of AMKL and TAM (Sato 1994). Establishes that AMKL/TAM blasts are immature, MEP-like progenitor cells with megakaryocytic differentiation potential.
PMID:26186939 — The biology of pediatric AMKL (review). Frames pediatric AMKL as 4-15% of childhood AML and identifies CBFA2T3-GLIS2 as the most frequent chimeric oncogene of non-DS pediatric AMKL.
PMID:12172547 — Wechsler 2002 (Nat Genet). Establishes near-universal acquired GATA1 mutations in DS-AMKL, with N-terminal premature stop codons preserving the GATA1s short isoform.
PMID:14636651 — Hitzler 2003 (Blood). Documents GATA1 mutations as initiating lesions in transient myeloproliferative disorder (TAM/TMD), and quantifies TAM incidence (~10% of DS newborns) and ~30% AMKL progression.
PMID:16166640 — Kuhl 2005 (Mol Cell Biol). IN_VITRO mouse fetal megakaryocyte study mechanistically dissecting GATA1 domain function. Removed during this revision because the snippet originally cited from this paper was background HUMAN_CLINICAL context already evidenced more directly by PMID:12172547. Cache file retained because the PMID is still cited here in the curation history.
PMID:15849773 — Hsiao 2005 (Am J Hematol). Defines the t(1;22)(p13;q13) RBM15-MKL1 (OTT-MAL) fusion oncogene and its restriction to infant/young child AMKL.
PMID:23153540 — Gruber 2012 (Cancer Cell). Identifies the cryptic inv(16)(p13.3q24.3) CBFA2T3-GLIS2 fusion in 27% of pediatric AMKL and shows in Drosophila and murine models that the fusion induces BMP signaling and enhances hematopoietic self-renewal.
PMID:28063190 — Masetti 2017 review of molecular profiles in pediatric non-DS AMKL. Establishes CBFA2T3-GLIS2 and NUP98-KDM5A as poor-prognosis recurrent fusions.
PMID:27114462 — de Rooij 2016 (Blood). Pediatric AMKL intergroup risk stratification on 153 cases: CBFA2T3-GLIS2 16%, RBM15-MKL1 12%, NUP98-KDM5A 9%, KMT2A-rearranged 9%, monosomy 7 6%; mutually exclusive; NUP98-KDM5A, CBFA2T3-GLIS2, KMT2A-rearranged, and monosomy 7 independently predict poor outcome.
PMID:28112737 — de Rooij 2017 (Nat Genet). Defines seven genomic subgroups of pediatric non-DS-AMKL by RNA + exome sequencing of 99 patients (75 pediatric, 24 adult), including the previously unrecognized HOX-rearranged (HOXr) subgroup (~14% of cases) with characteristic activating MPL mutations and superior clinical outcomes. Quantifies cooperating mutations in JAK/STAT (16.9%), cohesin/CTCF (18.1%), RAS pathway (15.7%), and MPL pathway, plus the near-universal RB1 deletion in NUP98-KDM5A AMKL.
PMID:28400376 — Uffmann 2017 (Blood). International ML-DS 2006 trial reporting superior outcomes with reduced-intensity chemotherapy in ML-DS, exploiting the heightened cytarabine sensitivity conferred by GATA1s and trisomy 21.

Curation Conclusions

The accepted disease model is that AMKL is heterogeneous in origin but convergent in output: a block of terminal megakaryocyte differentiation with retained megakaryoblast self-renewal, plus marrow stromal fibrosis driven by megakaryocyte-derived growth factors. Two clinically distinct contexts dominate: (1) Down syndrome-associated myeloid leukemia (ML-DS), driven by GATA1 truncating mutations on a constitutional trisomy 21 background and preceded by transient abnormal myelopoiesis; and (2) non-DS AMKL, dominated in infants by the t(1;22) RBM15-MKL1 fusion and in older children by the recurrent fusion oncogenes CBFA2T3-GLIS2 (most common, very poor prognosis), NUP98-KDM5A (high relapse risk, near-universal cooperating RB1 loss), KMT2A rearrangements, and HOX-cluster fusions (HOXr; ~14%, favorable prognosis with cooperating MPL mutations). Cooperating SNVs/indels in JAK/STAT, cohesin/CTCF, and RAS pathways further stratify outcome within fusion subgroups. Treatment is risk-adapted: reduced-intensity cytarabine-based chemotherapy for ML-DS (5-year OS approaching 90%), full intensity multi-agent AML induction for non-DS AMKL with allogeneic HSCT in first remission considered for high-risk fusion subgroups.

The curation reflects this model with structured pathophysiology nodes for each major fusion oncogene, a node for cooperating mutations, an accumulation/marrow failure node, structured subtypes with MONDO grounding where available, and treatment evidence. The originally cited PMID:16166640 IN_VITRO evidence item was removed because its snippet conveyed HUMAN_CLINICAL background context that is more appropriately and directly evidenced by PMID:12172547.

Acute Megakaryoblastic Leukemia

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References & Deep Research

References

Deep Research

Acute Megakaryoblastic Leukemia Deep Research Fallback

Provider Attempts

Evidence Scope Used For Curation

Curation Conclusions