Acute Myeloid Leukemia with CEBPA Somatic Mutations

MONDO:0017894 Pathograph 25 Show in embeddings browser acute myeloid leukemia

Acute myeloid leukemia with CEBPA somatic mutations (MONDO:0017894) is scoped here to non-familial AML in which the relevant CEBPA lesion or lesions are acquired. WHO-HAEM5 and ICC 2022 use different diagnostic boundaries, and neither boundary is interchangeable with ELN genetic-risk assignment. WHO recognizes AML with biallelic CEBPA or a single bZIP-region mutation and retains a 20% blast threshold; ICC recognizes AML with an in-frame bZIP CEBPA mutation from 10% blasts. Separately, ELN 2022 assigns in-frame bZIP CEBPA AML to favorable genetic risk for intensively treated adults irrespective of monoallelic or biallelic occurrence. Pooled outcome data nevertheless localize the reproducible favorable-survival signal to bZIP in-frame indels, so formal classification inclusion and observed prognostic subgroup should not be conflated. Acquired CEBPA lesions perturb the p42/p30 isoform balance or bZIP DNA-binding/dimerization functions, causing abnormal transcription, granulocytic differentiation arrest, leukemic progenitor expansion, blast accumulation, and marrow failure. Germline CEBPA predisposition is a separate qualifying context and cannot be excluded from diagnostic marrow variant allele fraction alone.

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2
Definitions
8
Pathophys.
1
Histopath.
9
Phenotypes
2
Hypotheses
3
Gaps
25
Pathograph
4
Genes
3
Variants
4
Medical Actions
2
Subtypes
7
Differentials
4
Trials
3
Models
7
References
1
Deep Research
🏷

Classifications

ICD-O Morphology
Leukemia
Harrison's Part
ONCOLOGY HEMATOLOGY
📘

Definitions

2
WHO-HAEM5 AML with CEBPA mutation definition
WHO-HAEM5 recognizes AML with biallelic CEBPA mutation or a single mutation in the bZIP region and retains a minimum 20% blast threshold for this entity. The local MONDO scope adds the requirement that the relevant CEBPA lesion or lesions be somatic rather than a germline-predisposition context.
DIAGNOSTIC_CRITERIA WHO Classification of Haematolymphoid Tumours, fifth edition
Show evidence (2 references)
PMID:35732831 SUPPORT Other
"include biallelic (biCEBPA) as well as single mutations located in the basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA)."
WHO-HAEM5 states the qualifying CEBPA patterns.
PMID:35732831 SUPPORT Other
"at least 20% blasts for diagnosis."
WHO-HAEM5 retains the 20% blast threshold for AML with CEBPA mutation.
ICC 2022 AML with in-frame bZIP CEBPA mutation definition
ICC recognizes AML with an in-frame bZIP CEBPA mutation at a minimum of 10% blasts, irrespective of allelic state. Pooled analyses describe current ICC recommendations as including bZIP missense variants; that classification boundary must not be equated with the narrower indel-specific favorable outcome or generalized to every CEBPA-mutated AML case.
DIAGNOSTIC_CRITERIA International Consensus Classification 2022
Show evidence (3 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"in-frame bZIP-mutation irrespective of double or single CEBPA-mutated status [12– 14] has been adapted in both ICC and the 2022 ELN recommendation"
The classification review describes the ICC shift to in-frame bZIP mutation irrespective of allelic state.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"In addition, ICC and ELN require a minimum of 10% blast for AML-CEBPA, whereas WHO-5 mandates 20% blast threshold."
The review directly contrasts the ICC and WHO blast thresholds.
PMID:38228680 SUPPORT Human Clinical
"ELN2022 and ICC recommendations (including CEBPA bZIPms)."
The pooled analysis documents that current ICC/ELN recommendations can include bZIP missense variants.
◆

Subtypes

2
AML with CEBPA bZIP in-frame insertion/deletion
CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
Narrow outcome-defined subgroup with an acquired in-frame insertion/deletion in the C-terminal CEBPA basic leucine zipper region. It overlaps the ICC entity and ELN 2022 favorable genetic-risk group but is not coextensive with their broader bZIP wording, which can include bZIP missense variants. The indel-specific favorable association is established most securely in intensively treated adults and does not eliminate relapse risk.
Show evidence (1 reference)
PMID:38228680 SUPPORT Human Clinical
"Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups."
The pooled cohort localizes the favorable outcome association to the bZIP in-frame-indel subgroup rather than every classification-included variant.
CEBPA-mutated AML outside the bZIP in-frame-indel subgroup
CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
Residual analytic category containing somatic CEBPA mutation patterns other than an in-frame bZIP insertion/deletion, including isolated TAD mutations, bZIP stop/frameshift mutations, and bZIP missense mutations. This is not a separately grounded ontology entity, and membership does not imply exclusion from every formal classification: current ICC/ELN recommendations can include bZIP missense variants, while WHO membership is broader still. The pooled outcome evidence does not extend the indel-specific favorable signal to the entire residual group.
Show evidence (2 references)
PMID:38228680 SUPPORT Human Clinical
"Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups."
The pooled cohort separates bZIP in-frame insertion/deletion cases from other CEBPA-mutant patterns on outcome.
PMID:38228680 SUPPORT Human Clinical
"ELN2022 and ICC recommendations (including CEBPA bZIPms)."
Current formal recommendations can include bZIP missense variants even though the pooled favorable-outcome signal was indel-specific.
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Mechanistic Hypotheses

2
Variant-specific CEBPA dysfunction converges on differentiation arrest
cebpa_variant_convergence CANONICAL
Evidence balance 1 support
N-terminal truncating lesions preserve and overproduce p30, whereas C-terminal bZIP lesions alter DNA binding and dimerization. These distinct molecular defects converge on abnormal granulocytic transcription, differentiation arrest, leukemic progenitor expansion, and AML.
Pathograph links
N-Terminal CEBPA p42-to-p30 Dysregulation -> Granulocytic Differentiation Arrest DIRECT Excess p30 disrupts transcription of granulocytic target genes and blocks maturation.
N-Terminal CEBPA p42-to-p30 Dysregulation -> Premalignant HSC and Leukemia-Initiating Progenitor Expansion INDIRECT KNOWN INTERMEDIATES Loss of p42-mediated control permits abnormal myeloid progenitor proliferation and leukemia initiation. Intermediates: p42 loss with retained p30 expression; loss of normal progenitor proliferation control
C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction -> Granulocytic Differentiation Arrest DIRECT Abnormal bZIP DNA binding and dimerization disrupt the CEBPA differentiation program.
C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction -> Premalignant HSC and Leukemia-Initiating Progenitor Expansion DIRECT C-terminal lesions expand premalignant long-term HSCs before overt leukemia.
Granulocytic Differentiation Arrest -> Premalignant HSC and Leukemia-Initiating Progenitor Expansion INDIRECT KNOWN INTERMEDIATES Arrested progenitors provide the cellular substrate for self-renewal and leukemic initiation. Intermediates: failure of terminal granulocytic maturation; persistence of committed myeloid progenitors
Premalignant HSC and Leukemia-Initiating Progenitor Expansion -> Leukemic Myeloblast Accumulation INDIRECT KNOWN INTERMEDIATES Expanded leukemia-initiating progenitors generate an overt myeloblast population. Intermediates: acquisition or selection of a leukemia-initiating clone
Leukemic Myeloblast Accumulation -> Leukemia DIRECT Expansion of a clonal myeloid blast population constitutes the leukemia phenotype.
Show evidence (1 reference)
PMID:11242107 SUPPORT In Vitro
"The mutant proteins block wild-type C/EBPalpha DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and fails to induce granulocytic differentiation."
Founding functional evidence connects human AML CEBPA mutations to dominant-negative differentiation failure.
Immune and mitochondrial expression state correlates with relapse risk
cebpa_high_risk_state EMERGING CEBPA bZIP In-Frame-Indel AML
Evidence balance 1 support
A subset of bZIP in-frame-indel AML shows interferon-signaling and mitochondrial expression programs associated with shorter event-free survival. The data are prognostic correlations; the direction and causal intermediates remain unresolved.
Show evidence (1 reference)
PMID:38253683 SUPPORT Human Clinical
"RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS)."
This supports association with outcome but not a causal pathway from CEBPA mutation to relapse.
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Discussions and Knowledge Gaps

3
How should WHO-HAEM5, ICC 2022, and ELN 2022 CEBPA categories be represented without conflating disease definition, blast threshold, allelic state, and treatment-context risk?
CONTROVERSY OPEN controversy_cebpa_classification_and_risk_boundaries
Attached to
definitions#WHO-HAEM5 AML with CEBPA mutation definition definitions#ICC 2022 AML with in-frame bZIP CEBPA mutation definition has_subtypes#CEBPA bZIP In-Frame-Indel AML
WHO includes biallelic CEBPA or a single bZIP mutation and retains 20% blasts; ICC requires an in-frame bZIP mutation and permits diagnosis from 10% blasts; ELN assigns in-frame bZIP CEBPA to favorable risk in intensively treated adults. These are overlapping but non-identical assertions, and newer outcome data suggest that in-frame bZIP indels, not every bZIP mutation, carry the clearest favorable signal.
Proposed experiments
Harmonized WHO-ICC-ELN prospective outcome analysis
exp_cebpa_harmonized_classification_outcomes
Prospectively phase full-length CEBPA variants and assign each case in parallel under WHO, ICC, and ELN rules, stratified by intensive versus lower-intensity treatment and serial flow MRD.
Decision criterion
A boundary is clinically coherent if it independently separates remission, relapse-free survival, and overall survival after adjustment for treatment, age, co-mutations, and MRD in external validation cohorts.
Show evidence (2 references)
PMID:35732831 SUPPORT Other
"include biallelic (biCEBPA) as well as single mutations located in the basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA)."
WHO-HAEM5 documents one diagnostic boundary.
PMID:38228680 SUPPORT Human Clinical
"Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups."
Pooled outcome data sharpen the favorable signal to bZIP in-frame insertion/deletion cases.
Which co-mutations or post-treatment MRD states identify in-frame bZIP CEBPA AML patients who benefit from transplantation in first remission?
CONTROVERSY OPEN controversy_cebpa_comutations_mrd_and_transplant
Attached to
genetic#WT1 genetic#DNMT3A genetic#FLT3-ITD diagnosis#Bone-Marrow Multiparameter Flow MRD Assessment treatments#Allogeneic Hematopoietic Stem Cell Transplantation
One intensively treated cohort associated WT1, DNMT3A, immune/metabolic expression, and upfront transplant with outcome, whereas a larger pooled analysis found no independent overall-survival effect from several co-mutations. Flow MRD during consolidation is prognostic, but there is no validated CEBPA-specific randomized rule for transplant in first remission.
Proposed experiments
Prospective MRD-adapted transplant strategy study
exp_cebpa_mrd_adapted_transplant_strategy
Enroll molecularly defined in-frame bZIP CEBPA AML, stratify by harmonized co-mutation profile and consolidation-time bone-marrow flow MRD, and compare chemotherapy consolidation with allogeneic transplantation in the prespecified high-risk/MRD-positive strata.
Decision criterion
A first-remission transplant rule would require a reproducible interaction showing improved overall survival, not only relapse reduction, with an acceptable non-relapse mortality tradeoff in an independent cohort.
Show evidence (2 references)
PMID:38253683 SUPPORT Human Clinical
"Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf."
This cohort supports one proposed adverse-risk signal.
PMID:38228680 SUPPORT Human Clinical
"co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS"
The pooled cohort provides a conflicting estimate, keeping a co-mutation-based transplant rule unresolved.
Do p30-only and paired Cebpa knock-in mice reproduce the variant-specific human bZIP in-frame-indel outcome subgroup and its treatment response?
HUMAN MODEL MISMATCH OPEN gap_cebpa_model_to_human_variant_fidelity
Attached to
pathophysiology#N-Terminal CEBPA p42-to-p30 Dysregulation pathophysiology#C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction
The mouse models establish etiologic and cellular effects of Cebpa isoform imbalance and paired terminal lesions, but human favorable risk is most clearly associated with diverse bZIP in-frame indels. The models do not reproduce the complete human allelic, co-mutation, immune/metabolic, and treatment-context landscape.
Proposed experiments
Isogenic human CEBPA variant-panel leukemia model
exp_cebpa_isogenic_human_variant_panel
Engineer representative N-terminal truncating, bZIP in-frame indel, bZIP stop, and bZIP missense alleles singly and in phased pairs in human CD34+ hematopoietic cells, with matched xenografts and drug-response profiling.
Decision criterion
Model fidelity would be supported if variant classes reproduce the human hierarchy of differentiation arrest, stem/progenitor state, transcriptome, chemotherapy sensitivity, and relapse-associated MRD in independent donors.
Show evidence (2 references)
PMID:18394553 SUPPORT Model Organism
"To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30."
The model deliberately isolates the N-terminal isoform consequence rather than the full human genotype spectrum.
PMID:19878871 SUPPORT Model Organism
"We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia."
The paired knock-in system provides mechanistic precedent but still abstracts heterogeneous human alleles.
⚙

Pathophysiology

8
N-Terminal CEBPA p42-to-p30 Dysregulation
Acquired N-terminal TAD frameshift or nonsense variants truncate the p42 isoform while permitting downstream translation reinitiation and excess p30. The retained p30 protein interferes with normal C/EBPalpha transcriptional control; this is a dominant-negative isoform imbalance rather than simple absence of the protein.
Variant-specific CEBPA dysfunction converges on differentiation arrest
hematopoietic multipotent progenitor cell CL:0000837 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic multipotent progenitor cell (CL:0000837). CL:0000837 is a cell type from the Cell Ontology.
CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Granulocytic Differentiation Arrest Excess p30 disrupts transcription of granulocytic target genes and blocks maturation. Variant-specific CEBPA dysfunction converges on differentiation arrest
Premalignant HSC and Leukemia-Initiating Progenitor Expansion Loss of p42-mediated control permits abnormal myeloid progenitor proliferation and leukemia initiation. Variant-specific CEBPA dysfunction converges on differentiation arrest
Show evidence (2 references)
PMID:11242107 SUPPORT In Vitro
"We found that five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream."
Human AML variants were shown to truncate p42 while preserving downstream p30 translation.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"the aberrant dominant-negative p30 isoform from the second protein translation initiation codon and thus suppress myeloid differentiation"
The review states the isoform-specific consequence of N-terminal lesions.
C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction
Acquired C-terminal bZIP in-frame indels or missense variants alter the DNA-binding and leucine-zipper dimerization region. In-frame bZIP indels are the prognostically favorable mutation class, but they remain leukemogenic lesions that disturb CEBPA-regulated transcription and lineage commitment.
Variant-specific CEBPA dysfunction converges on differentiation arrest
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Granulocytic Differentiation Arrest Abnormal bZIP DNA binding and dimerization disrupt the CEBPA differentiation program. Variant-specific CEBPA dysfunction converges on differentiation arrest
Premalignant HSC and Leukemia-Initiating Progenitor Expansion C-terminal lesions expand premalignant long-term HSCs before overt leukemia. Variant-specific CEBPA dysfunction converges on differentiation arrest
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"the C-terminal/bZIP in-frame indels or missense mutations disrupt protein dimerization and DNA binding."
The full-text review states the bZIP functional consequence.
Granulocytic Differentiation Arrest
Variant-specific failure of CEBPA transcription prevents normal granulocytic maturation. Immature myeloid progenitors persist instead of completing the neutrophil differentiation program.
Variant-specific CEBPA dysfunction converges on differentiation arrest
myeloblast CL:0000835 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloblast (CL:0000835). CL:0000835 is a cell type from the Cell Ontology.
granulocyte differentiation GO:0030851 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased granulocyte differentiation (GO:0030851). GO:0030851 is a biological process from the Gene Ontology. ↓ DECREASED
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Premalignant HSC and Leukemia-Initiating Progenitor Expansion Arrested progenitors provide the cellular substrate for self-renewal and leukemic initiation. Variant-specific CEBPA dysfunction converges on differentiation arrest
Show evidence (1 reference)
PMID:11242107 SUPPORT In Vitro
"Ours is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML."
Human AML functional evidence identifies differentiation arrest as the consequence of CEBPA mutation.
Premalignant HSC and Leukemia-Initiating Progenitor Expansion
C-terminal lesions can expand premalignant long-term HSCs, while N-terminal lesions preserve committed myeloid progenitors that can become leukemia-initiating cells. Combined N- and C-terminal lesions incorporate both properties and accelerate disease development.
Variant-specific CEBPA dysfunction converges on differentiation arrest
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology. granulocyte monocyte progenitor cell CL:0000557 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte monocyte progenitor cell (CL:0000557). CL:0000557 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Leukemic Myeloblast Accumulation Expanded leukemia-initiating progenitors generate an overt myeloblast population. Variant-specific CEBPA dysfunction converges on differentiation arrest
Show evidence (1 reference)
PMID:19878871 SUPPORT Model Organism
"The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations."
The knock-in model demonstrates complementary cellular effects of the classic double-mutant pattern.
Leukemic Myeloblast Accumulation
Leukemic myeloblasts expand in bone marrow and may circulate in blood. This establishes the acute leukemic state and creates a marrow environment that suppresses normal downstream hematopoietic production.
Variant-specific CEBPA dysfunction converges on differentiation arrest
myeloblast CL:0000835 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloblast (CL:0000835). CL:0000835 is a cell type from the Cell Ontology.
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology. blood UBERON:0000178 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood (UBERON:0000178). UBERON:0000178 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Leukemia Expansion of a clonal myeloid blast population constitutes the leukemia phenotype. Variant-specific CEBPA dysfunction converges on differentiation arrest
Leukocytosis Circulating blast burden can produce an elevated total leukocyte count.
Suppression of Normal Hematopoiesis The leukemic marrow environment impedes production of downstream normal blood cells.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"at least 20% blasts for diagnosis."
WHO establishes an overt blast threshold for this genetic AML entity.
Suppression of Normal Hematopoiesis
The AML marrow environment impedes normal differentiation downstream of the hematopoietic stem-cell compartment. Reduced erythroid, megakaryocytic, and granulocytic output produces multilineage or lineage-specific cytopenias.
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pancytopenia Multilineage suppression can reduce erythrocytes, platelets, and neutrophils together.
Anemia Suppressed erythroid production lowers circulating red-cell mass.
Thrombocytopenia Suppressed megakaryocytic output lowers the platelet count.
Neutropenia Suppressed granulocytic output lowers mature neutrophil production.
Cytopenia-Associated Complications Lineage-specific cytopenias lead to fatigue, bleeding, and infection susceptibility.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition."
Patient marrow analysis and xenografts support impaired normal downstream production.
Cytopenia-Associated Complications
Anemia contributes to fatigue, thrombocytopenia produces bruising or bleeding, and neutropenia increases bacterial and fungal infection risk. These are AML-wide consequences rather than distinctive CEBPA-subtype features.
blood UBERON:0000178 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood (UBERON:0000178). UBERON:0000178 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Fatigue Anemia and systemic leukemia burden contribute to fatigue.
Abnormal Bleeding Reduced platelet production increases bruising and hemorrhage risk.
Recurrent Infections Reduced mature neutrophil production increases susceptibility to severe infection.
Show evidence (1 reference)
DOI:10.1002/ajh.26822 SUPPORT Other
"Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding."
The review identifies the major cytopenia-associated AML complications.
Correlated IFN and Mitochondrial High-Risk State
Within the CEBPA bZIP in-frame-indel analytic subgroup, a subset has increased interferon-stimulated and mitochondrial-complex gene expression associated with shorter event-free survival. This node is explicitly an emerging, correlation-based risk hypothesis rather than a settled causal CEBPA mechanism.
type I interferon-mediated signaling pathway GO:0060337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:38253683 SUPPORT Human Clinical
"Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival"
The cohort supports a prognostic association, not causal direction.
✶

Histopathology

1
Myeloblast Predominance
AML diagnosis is based on accumulation of myeloblasts in blood or bone marrow, with CEBPA mutation status defining this molecularly specified subtype.
Show evidence (1 reference)
PMID:23590662 SUPPORT Other
"myeloblasts in the blood or bone marrow."
The abstract directly states that AML is characterized by myeloblasts in blood or bone marrow.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acute Myeloid Leukemia with CEBPA Somatic Mutations Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Blood 7
Leukemia HP:0001909 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukemia (HP:0001909). HP:0001909 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"at least 20% blasts for diagnosis."
WHO explicitly recognizes an AML entity defined by CEBPA mutation and an overt blast threshold.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition."
This supports multilineage cytopenia mechanistically but does not quantify pancytopenia in CEBPA-mutated AML.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/ajh.26822 SUPPORT Other
"Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding."
The AML review directly identifies anemia as a clinical manifestation.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs"
Reduced downstream hematopoietic production supports thrombocytopenia indirectly; no CEBPA-specific frequency is inferred.
Neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs"
Reduced downstream hematopoietic production supports neutropenia indirectly; no CEBPA-specific frequency is inferred.
Leukocytosis Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytosis, annotated with Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34320176 SUPPORT Human Clinical
"patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis"
This large cohort directly supports higher diagnostic WBC counts in the main CEBPA-defined groups.
Abnormal Bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding."
The study directly links AML marrow failure to bleeding risk.
Immune 1
Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23901108 SUPPORT Human Clinical
"Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding."
The study supports infection susceptibility, while the HPO term's recurrent wording is broader than the source.
Constitutional 1
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30131851 SUPPORT Human Clinical
"Fatigue is one of the most commonly reported symptoms of AML."
A prospective untreated-AML cohort directly supports fatigue as a common presenting symptom.
🧬

Genetic Associations

4
CEBPA (Somatic driver mutation defining AML-CEBPA)
Gene: CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37261703 SUPPORT Other
"CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic and familial AML."
This review supports CEBPA mutation as a recurrent genetic alteration in AML and frames the sporadic/familial distinction.
Variants (2)
N-terminal CEBPA truncating mutation with retained p30 translation
Gene: CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee. truncating variant
Somatic N-terminal TAD frameshift or nonsense variants truncate p42 while preserving downstream p30 translation, producing a dominant-negative isoform imbalance and impaired granulocytic transcription.
Functional effects
CEBPA transcriptional regulation of granulocytic differentiation dominant-negative isoform imbalance
Loss of p42 with retained p30 blocks wild-type DNA binding and transactivation.
Show evidence (1 reference)
PMID:11242107 SUPPORT In Vitro
"five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream."
Functional human AML evidence establishes the p42-truncation/p30-retention pattern.
C-terminal CEBPA bZIP in-frame insertion-deletion
Gene: CEBPA hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CEBPA (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee. inframe indel
Somatic in-frame insertions or deletions in the C-terminal bZIP region disrupt DNA binding and dimerization. This variant class, rather than all CEBPA variants, carries the reproducible favorable-risk association.
Functional effects
CEBPA DNA binding and dimerization altered transcription-factor function
bZIP structural alteration disrupts DNA binding and protein dimerization.
Show evidence (1 reference)
PMID:34320176 SUPPORT Human Clinical
"the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf)."
The large cohort identifies the bZIP in-frame class as the outcome-defining variant pattern.
WT1 (Cohort-dependent prognostic co-mutation in CEBPA bZIP in-frame-indel AML)
Gene: WT1 hgnc:12796 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WT1 (hgnc:12796). hgnc:12796 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: SOMATIC
Show evidence (2 references)
PMID:38253683 SUPPORT Human Clinical
"Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf."
This cohort found an adverse WT1 association, supporting one side of a conflicting literature.
PMID:38228680 SUPPORT Human Clinical
"co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS"
A larger pooled analysis did not find an independent OS effect, so WT1 is not encoded as a settled transplant trigger.
DNMT3A (Reported adverse prognostic co-mutation with unresolved replication)
Gene: DNMT3A hgnc:2978 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNMT3A (hgnc:2978). hgnc:2978 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: SOMATIC
Show evidence (2 references)
PMID:38253683 SUPPORT Human Clinical
"Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf."
This cohort supports an adverse association, but it does not establish a universal independent effect.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"results are likely attributable to the small sample sizes limiting the analysis power."
The review explicitly characterizes co-mutation prognostic results as controversial.
FLT3-ITD (Cohort-dependent adverse prognostic co-mutation in some CEBPA-mutated AML contexts)
Gene: FLT3 hgnc:3765 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLT3 (hgnc:3765). hgnc:3765 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: SOMATIC
Show evidence (2 references)
PMID:36701843 SUPPORT Human Clinical
"For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes."
This human cohort supports adverse association in one normal-karyotype setting.
PMID:38228680 SUPPORT Human Clinical
"co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS"
The pooled analysis did not reproduce an independent OS effect, establishing uncertainty.
Variants (1)
FLT3 internal tandem duplication
Gene: FLT3 hgnc:3765 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in FLT3 (hgnc:3765). hgnc:3765 is a gene from the HUGO Gene Nomenclature Committee. internal tandem duplication
Somatic FLT3 internal tandem duplication reported as an adverse marker in some CEBPA-mutated cohorts.
Show evidence (1 reference)
PMID:36701843 SUPPORT Human Clinical
"FLT3-ITDpos was associated with worse outcomes."
The normal-karyotype cohort reports the adverse FLT3-ITD association.
💊

Medical Actions

4
Intensive Anthracycline- and Cytarabine-Based Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: cytarabine CHEBI:28680 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cytarabine (CHEBI:28680). CHEBI:28680 is a therapeutic agent from Chemical Entities of Biological Interest. daunorubicin CHEBI:41977 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses daunorubicin (CHEBI:41977). CHEBI:41977 is a therapeutic agent from Chemical Entities of Biological Interest.
Medically fit patients are generally treated with anthracycline- and cytarabine-based induction followed by cytarabine-containing consolidation. This is an AML treatment backbone, not a CEBPA-directed therapy. The favorable reproducible favorable-outcome evidence applies most securely to bZIP in-frame-indel disease treated intensively; it does not establish that every classification-included bZIP variant responds equivalently.
Mechanism Target:
INHIBITS Leukemic Myeloblast Accumulation — Cytotoxic induction and consolidation reduce the proliferating leukemic blast population.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"The anthracycline and cytarabine based induction chemotherapy followed by consolidation"
The CEBPA-focused review identifies intensive induction and consolidation as the principal treatment backbone for fit patients.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"The anthracycline and cytarabine based induction chemotherapy followed by consolidation"
This supports the standard intensive AML backbone without treating an unreported trial result as efficacy evidence.
Hypomethylating Agent Plus Venetoclax for Intensive-Therapy-Ineligible Patients
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: venetoclax CHEBI:133021 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses venetoclax (CHEBI:133021). CHEBI:133021 is a therapeutic agent from Chemical Entities of Biological Interest. azacitidine NCIT:C288 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses azacitidine (NCIT:C288). NCIT:C288 is a therapeutic agent from the NCI Thesaurus.
A hypomethylating agent plus venetoclax is a lower-intensity frontline AML option when age, frailty, or comorbidity precludes intensive chemotherapy. CEBPA-specific evidence is limited: favorable-risk AML was excluded from VIALE-A, and the reported CEBPA double-mutated experience is a small subset. The addition of low-dose cytarabine is being studied and is not encoded as established standard care for this molecular subtype.
Mechanism Target:
INHIBITS Leukemic Myeloblast Accumulation — The combination is used to reduce the leukemic blast population in patients unable to receive intensive induction.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"Recently, hypomethylating agents (HMA) coupled with venetoclax have been adapted as frontline therapy for patients who are not eligible for high intensity chemotherapy"
The review supports use of the lower-intensity combination to treat the leukemic disease in intensive-therapy-ineligible patients.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"Recently, hypomethylating agents (HMA) coupled with venetoclax have been adapted as frontline therapy for patients who are not eligible for high intensity chemotherapy"
The review supports this as an eligibility-based lower-intensity AML approach.
DOI:10.1007/s11899-023-00699-3 SUPPORT Human Clinical
"The complete remission (CR) and complete remission with incomplete count recovery (CRi) rate in this patient population were 75%."
A small reported CEBPA double-mutated subset supports activity but cannot establish subtype-specific comparative efficacy.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089
Retrospective double-mutated CEBPA cohorts found improved relapse-free but not overall survival from transplantation in first complete remission and support reserving allogeneic transplantation for refractory disease, relapse, or second remission. Whether co-mutations or post-treatment MRD identify a first-remission subgroup with an overall-survival benefit remains unresolved and is represented below as an open discussion, not a recommendation. Suspected germline CEBPA predisposition requires constitutional evaluation before related-donor selection.
Mechanism Target:
INHIBITS Leukemic Myeloblast Accumulation — Conditioning and donor hematopoiesis provide cytoreduction and a graft-versus-leukemia effect in selected high-risk or relapsed settings.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"This study provided evidence to reserve hematopoietic stem cell transplant to CR2 or refractory disease."
The review supports transplant as an anti-leukemia strategy in selected later or refractory settings.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"While both autologous and allogeneic stem cell transplant provide improved RFS in CR1, the OS was not different compared to patient who received chemotherapy only. This study provided evidence to reserve hematopoietic stem cell transplant to CR2 or refractory disease."
The review supports a limited CR1 role and later transplant use rather than routine upfront transplantation for favorable-risk disease.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"This information is important for patient management including allogeneic stem cell transplant donor selection as well as patient family consultation and surveillance."
Germline-versus-somatic assignment is clinically consequential for donor selection.
Supportive Care for Cytopenias and Infection Risk
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Supportive management includes red-cell and platelet transfusion when clinically indicated, prompt evaluation and treatment of infection, and individualized measures for disease- and therapy-associated cytopenias. These measures treat complications but do not eradicate the CEBPA-mutant clone.
Target Phenotypes: Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology. Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology. Neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology. Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology. Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23901108 SUPPORT Human Clinical
"Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding."
Human AML marrow failure establishes the complications that supportive care addresses.
PMID:34307165 SUPPORT Other
"chemotherapy-induced myelosuppression is managed with chemotherapy dose delays/reductions and lineage-specific supportive care interventions, such as hematopoietic growth factors and blood transfusions."
This oncology supportive-care review directly supports transfusion and lineage-specific management of treatment-associated myelosuppression.
🔬

Diagnosis

7
Complete Blood Count and Peripheral Blood Smear
CBC and smear assess anemia, thrombocytopenia, neutropenia or leukocytosis and identify circulating blasts. The pattern establishes urgency and supports AML evaluation but is not specific for CEBPA-mutated disease.
complete blood count NCIT:C28133 NCI Thesaurus (NCIT)
Results: Cytopenias or leukocytosis with circulating myeloblasts may be present.
Show evidence (1 reference)
PMID:34320176 SUPPORT Human Clinical
"patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis"
The cohort supports CBC-detectable WBC elevation in major CEBPA-defined groups.
Bone Marrow Morphology and Blast Enumeration
Aspirate and core biopsy establish an acute myeloid blast process, assess maturation and dysplasia, and supply material for flow, cytogenetic, and molecular studies. Apply the classification-specific threshold: WHO-HAEM5 requires at least 20% blasts for AML with CEBPA mutation, whereas ICC uses at least 10% for its in-frame bZIP entity.
biopsy of bone marrow NCIT:C15193 NCI Thesaurus (NCIT)
Results: An acute myeloid blast proliferation meeting the selected WHO or ICC threshold.
Show evidence (2 references)
PMID:35732831 SUPPORT Other
"at least 20% blasts for diagnosis."
WHO directly establishes the CEBPA-entity blast threshold.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"ICC and ELN require a minimum of 10% blast for AML-CEBPA, whereas WHO-5 mandates 20% blast threshold."
The classification review states the ICC-versus-WHO threshold difference.
Flow-Cytometric Myeloid Lineage Assessment
Multiparameter flow cytometry confirms an acute myeloid immunophenotype and establishes a leukemia-associated phenotype for later MRD assessment. CEBPA double-mutated blasts frequently express CD7, CD15, and HLA-DR, but no immunophenotype substitutes for sequencing.
flow cytometry procedure NCIT:C16585 NCI Thesaurus (NCIT)
Results: Myeloid blasts with a reproducible leukemia-associated immunophenotype.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"frequency of CD7, CD15, and HLA-DR expression"
The review summarizes the characteristic but non-pathognomonic flow phenotype.
Cytogenetic and Broad Myeloid Molecular Profiling
Karyotyping/FISH and broad myeloid NGS identify competing AML-defining lesions, myelodysplasia-related abnormalities, and co-mutations that affect integrated risk. A normal karyotype is common but is not a diagnostic requirement.
cytogenetic analysis NCIT:C18280 NCI Thesaurus (NCIT)
Results: Cytogenetic and co-mutation profile used for diagnostic hierarchy and risk assignment.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"CEBPAdm is strongly associated with a normal karyotype"
The review supports cytogenetic assessment while showing that CEBPA AML is often karyotypically normal.
Full-Length CEBPA Sequencing and Variant Annotation
Sequence the full single-exon CEBPA coding region and report domain, insertion/deletion frame, variant allele fraction, and co-occurring CEBPA lesions. Capture-based NGS is preferred over amplicon-only methods because the locus is GC-rich and indel-heavy. Routine short reads may not phase distant N- and C-terminal variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Precise CEBPA mutation pattern supporting WHO/ICC assignment and ELN risk classification.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"method for CEBPA mutation detection is full length sequencing of this single exon gene."
The review directly recommends full-length sequencing.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"Capture-based NGS has been shown to perform better than amplicon-based NGS in CEBPA mutation detection"
This supports the assay-design recommendation for the GC-rich, indel-prone locus.
Constitutional Evaluation for Germline CEBPA Predisposition
Evaluate germline predisposition when the CEBPA variant persists in complete remission, onset or family history is suggestive, or donor selection makes constitutional status consequential. Marrow or blood VAF near 50% cannot distinguish germline from somatic disease. Cultured skin fibroblasts are the preferred constitutional specimen; related donors require appropriate testing and counseling.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Constitutional testing distinguishes this somatic-only entry from germline CEBPA-associated predisposition.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"VAF cannot be reliably used as a marker"
This directly refutes using diagnostic blood or marrow VAF alone to assign origin.
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"The gold standard constitutional sample type for germline confirmation is cultured skin fibroblasts"
The review identifies the preferred constitutional specimen.
Bone-Marrow Multiparameter Flow MRD Assessment
Assess MRD using bone-marrow multiparameter flow after therapy, especially during consolidation, and interpret it with integrated genetic risk. Persisting CEBPA sequence alone is not automatically residual leukemia because it can indicate a constitutional variant.
flow cytometry procedure NCIT:C16585 NCI Thesaurus (NCIT)
Results: MRD category used for dynamic relapse-risk and transplant assessment.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"MRD-positive status during consolidation but not after induction was associated with an increased risk of relapse and decreased relapse free survival."
The CEBPA review supports consolidation-time MFC-MRD as prognostic.
PMID:41397238 SUPPORT Other
"MRD recommendations are tailored to individual prognostic and genetic subgroups."
Current ELN-DAVID consensus supports genotype-aware MRD interpretation.
📈

Progression

4
Diagnosis and Classification Assignment
Establish AML, apply the selected WHO or ICC blast threshold, identify the precise CEBPA domain and variant type, and distinguish disease definition from ELN treatment-context risk assignment. Diagnostic marrow VAF cannot by itself establish somatic origin.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"include biallelic (biCEBPA) as well as single mutations located in the basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA)."
WHO shows why exact mutation pattern is part of disease assignment.
Induction and Complete Remission
CEBPA bZIP In-Frame-Indel AML
Fit patients usually receive intensive induction. The bZIP in-frame-indel subgroup has higher complete-remission rates and better survival than other CEBPA mutation patterns, but this prognostic association does not eliminate relapse risk.
Show evidence (1 reference)
PMID:38228680 SUPPORT Human Clinical
"Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups."
The pooled analysis identifies the response and survival advantage of the in-frame bZIP subgroup.
Consolidation and MRD Reassessment
Bone-marrow multiparameter-flow MRD during consolidation refines relapse risk. CEBPA mutation detection is not automatically an MRD assay because a persisting variant can indicate germline predisposition; interpret molecular findings with remission tissue and broader clonality context.
Show evidence (2 references)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"MRD-positive status during consolidation but not after induction was associated with an increased risk of relapse and decreased relapse free survival."
The CEBPA review summarizes the prognostic timing of flow-cytometric MRD.
PMID:41397238 SUPPORT Other
"Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key end point in clinical trials."
Current ELN-DAVID consensus establishes MRD as a dynamic AML management tool.
Relapsed or Refractory Disease
Relapsed CEBPA double-mutated AML can remain chemotherapy-sensitive. Reinduction, molecular reassessment, MRD response, donor suitability, and overall AML risk inform allogeneic transplantation in second remission or refractory disease.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"The second CR rate was reported to be 83–85% [78, 79]."
The review supports retained chemosensitivity after relapse in double-mutated disease.
🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Acute Myeloid Leukemia with CEBPA Somatic Mutations:

Germline CEBPA-Associated Myeloid Neoplasm Predisposition
Overlapping Features Familial or de novo constitutional CEBPA pathogenic variants can produce AML with a second acquired CEBPA lesion and can closely resemble sporadic double-mutated disease.
Distinguishing Features
  • Persistence of a CEBPA variant in complete remission supports constitutional evaluation.
  • Diagnostic blood or marrow VAF near 50% is not sufficient to distinguish origin.
  • Cultured skin fibroblast testing, family evaluation, and genetic counseling establish constitutional status.
Show evidence (1 reference)
DOI:10.1007/s11899-023-00699-3 SUPPORT Other
"the persistence of a CEBPA mutation at the time of complete remission warrants"
Persistence in remission is a direct trigger for germline evaluation even without family history.
Acute Myeloid Leukemia with Mutated NPM1 MONDO:0044923
Overlapping Features A separate mutation-defined AML entity that may present with similar acute myeloid morphology.
Distinguishing Features
  • A defining NPM1 mutation and application of the WHO/ICC diagnostic hierarchy distinguish this entity.
  • NPM1 co-mutation is uncommon in the biallelic and single-bZIP CEBPA groups.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"include AML with NPM1 and AML with CEBPA mutation."
WHO lists NPM1-mutated and CEBPA-mutated AML as separate mutation-defined types.
Acute Promyelocytic Leukemia with PML::RARA MONDO:0012883
Overlapping Features A genetically defined AML emergency that can overlap in cytopenic acute-leukemia presentation.
Distinguishing Features
  • Promyelocytic morphology, coagulopathy, and PML::RARA testing distinguish APL and require immediate disease-specific management.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"criteria for AML with PML::RARA, AML with RUNX1::RUNX1T1, and AML with CBF::MYH11"
WHO recognizes these as distinct AML types requiring lesion-specific assignment.
Core-Binding-Factor Acute Myeloid Leukemia
Overlapping Features RUNX1::RUNX1T1- or CBFB::MYH11-defined AML can share an acute myeloid blast presentation.
Distinguishing Features
  • Fusion testing identifies a core-binding-factor lesion and redirects classification and risk assessment.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion Acute myeloid leukaemia with CBFB::MYH11 fusion"
WHO lists the two core-binding-factor AML types separately.
Myelodysplastic Syndrome or ICC MDS/AML MONDO:0018881
Overlapping Features Cytopenia, dysplasia, and 10-19% blasts can overlap at the MDS/AML boundary.
Distinguishing Features
  • Apply the selected classification's blast threshold and CEBPA mutation-pattern requirements.
  • WHO retains 20% blasts for AML with CEBPA mutation, whereas ICC permits its in-frame bZIP entity from 10% blasts.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"retaining a 20% blast cutoff to delineate MDS from AML."
WHO describes the retained general boundary that must be reconciled with genetic-entity exceptions.
Mixed-Phenotype Acute Leukemia
Overlapping Features Acute leukemia of ambiguous lineage can overlap when blasts express cross-lineage markers.
Distinguishing Features
  • Formal lineage criteria and flow/cytochemical evidence of more than one lineage distinguish MPAL.
  • A CEBPA mutation alone does not replace lineage assignment.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"Mixed-phenotype acute leukaemia, B/myeloid"
WHO-HAEM5 recognizes MPAL as a separate ambiguous-lineage category.
🔬

Clinical Trials

4
NCT06458257 NOT_APPLICABLE RECRUITING
Recruiting observational study evaluating outcomes after allogeneic transplantation following induction and consolidation in newly diagnosed patients labeled high-relapse-risk CEBPA-mutant AML. It is not randomized and has no posted results, so efficacy is not established.
Show evidence (1 reference)
clinicaltrials:NCT06458257 SUPPORT Human Clinical
"To access whether the therapeutic regimen is effective for high-relapse-risk CEBPA mutant acute myeloid leukemia, the disease-free-survival (DFS), overall survival (OS), non-relapse-mortality of patients is evaluated."
The registry states the planned outcomes; it does not provide an efficacy result.
NCT06529250 NOT_APPLICABLE RECRUITING
Recruiting open-label randomized study comparing intermediate-dose HAD with a conventional regimen in CEBPA-mutated AML. The registry reports no results; superiority remains a study hypothesis.
Show evidence (1 reference)
clinicaltrials:NCT06529250 SUPPORT Human Clinical
"Therefore, this project intends to confirm the efficacy of intermediate-dose HAD in the treatment of CEBPA double-mutated AML is superior to the conventional treatment regimen through the multi-center RCT study."
The trial summary describes the intended randomized comparison, not a completed result.
NCT04415008 PHASE_II ACTIVE_NOT_RECRUITING
Active-not-recruiting prospective multicenter single-arm phase 2 study of HAD induction with intensified cytarabine in newly diagnosed CEBPA double-mutated AML. No results are posted in the registry.
Show evidence (1 reference)
clinicaltrials:NCT04415008 SUPPORT Human Clinical
"HAD(homoharringtonine(HHT)+cytarabine+daunorubicin) with intermediate dose cytarabine improved the survival of AML, especially in patients with CEBPA double mutation."
The registry text supplies the study rationale; the single-arm study has not posted results.
NCT07451912 RECRUITING
Recruiting open-label single-arm phase 1/2 study of venetoclax plus a hypomethylating agent and low-dose subcutaneous cytarabine for adults with newly diagnosed CEBPA-mutated AML who cannot tolerate intensive chemotherapy. It has no posted results and the triplet remains investigational.
Show evidence (1 reference)
clinicaltrials:NCT07451912 SUPPORT Human Clinical
"The goal of this clinical trial is to learn if a treatment combination-venetoclax plus hypomethylating agents (like azacitidine or decitabine) and low-dose cytarabine-works to treat adults with newly diagnosed CEBPA-mutated acute myeloid leukemia (AML) who can't tolerate intensive chemotherapy."
The registry defines the investigational triplet and intensive-therapy-ineligible study population.
🐁

Animal Models

3
Cebpa p30-only knock-in with loss of the p42 isoform Mus musculus
A p30-only knock-in models the N-terminal human mutation consequence by removing p42 while retaining p30. Mice develop AML with complete penetrance and yield transplantable committed myeloid leukemia-initiating cells. The model isolates isoform imbalance and does not reproduce the common paired N-terminal plus bZIP genotype or the full human co-mutation landscape.
Species
Mus musculus
Genotype
Cebpa p30-only knock-in with loss of the p42 isoform
Genes
Cebpa hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns Cebpa (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:18394553 SUPPORT Model Organism
"we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance."
The engineered model directly tests the p42-loss/p30-retention mechanism and develops AML.
Combined N-terminal and C-terminal Cebpa knock-in mutations Mus musculus
Complementary Cebpa knock-in alleles model the classic paired mutation architecture. C-terminal lesions expand premalignant long-term HSCs, while N-terminal lesions allow committed myeloid leukemia-initiating progenitors; the combined genotype accelerates disease. Exact alleles and treatment context still differ from the heterogeneous human bZIP in-frame entity.
Species
Mus musculus
Genotype
Combined N-terminal and C-terminal Cebpa knock-in mutations
Genes
Cebpa hgnc:1833 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns Cebpa (hgnc:1833). hgnc:1833 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:19878871 SUPPORT Model Organism
"The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations."
The paired knock-in experiment demonstrates complementary mutation effects and accelerated leukemogenesis.
cebpa loss-of-function and N-terminal zP30-expressing mutants Danio rerio
Zebrafish cebpa mutants resolve developmental HSPC generation and isoform function. N-terminal zP30 mutants impair myeloid differentiation without reducing HSPC number. This is a developmental hematopoiesis model, not an AML model, and it should not be used as evidence of leukemia penetrance or therapy.
Species
Danio rerio
Genotype
cebpa loss-of-function and N-terminal zP30-expressing mutants
Show evidence (1 reference)
PMID:39500381 SUPPORT Model Organism
"while myeloid differentiation was impaired in cebpa N-terminal mutants expressing the truncated zP30 protein, the number of HSPCs was not affected"
The developmental model separates an N-terminal isoform effect on myeloid differentiation from HSPC abundance.
{ }

Source YAML

click to show 
name: Acute Myeloid Leukemia with CEBPA Somatic Mutations
creation_date: "2026-05-11T12:14:38Z"
description: >-
  Acute myeloid leukemia with CEBPA somatic mutations (MONDO:0017894) is scoped
  here to non-familial AML in which the relevant CEBPA lesion or lesions are
  acquired. WHO-HAEM5 and ICC 2022 use different diagnostic boundaries, and
  neither boundary is interchangeable with ELN genetic-risk assignment. WHO
  recognizes AML with biallelic CEBPA or a single bZIP-region mutation and
  retains a 20% blast threshold; ICC recognizes AML with an in-frame bZIP CEBPA
  mutation from 10% blasts. Separately, ELN 2022 assigns in-frame bZIP CEBPA AML
  to favorable genetic risk for intensively treated adults irrespective of
  monoallelic or biallelic occurrence. Pooled outcome data nevertheless localize
  the reproducible favorable-survival signal to bZIP in-frame indels, so formal
  classification inclusion and observed prognostic subgroup should not be
  conflated. Acquired CEBPA lesions perturb the p42/p30 isoform balance or bZIP
  DNA-binding/dimerization functions, causing abnormal transcription,
  granulocytic differentiation arrest, leukemic progenitor expansion, blast
  accumulation, and marrow failure. Germline CEBPA predisposition is a separate
  qualifying context and cannot be excluded from diagnostic marrow variant
  allele fraction alone.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
has_subtypes:
- name: CEBPA bZIP In-Frame-Indel AML
  display_name: AML with CEBPA bZIP in-frame insertion/deletion
  description: >-
    Narrow outcome-defined subgroup with an acquired in-frame insertion/deletion
    in the C-terminal CEBPA basic leucine zipper region. It overlaps the ICC
    entity and ELN 2022 favorable genetic-risk group but is not coextensive with
    their broader bZIP wording, which can include bZIP missense variants. The
    indel-specific favorable association is established most securely in
    intensively treated adults and does not eliminate relapse risk.
  genes:
  - preferred_term: CEBPA
    term:
      id: hgnc:1833
      label: CEBPA
  evidence:
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only bZIPInDel patients had significantly higher rates of complete
      remission and longer relapse free and overall survival (OS) compared with
      all other CEBPA-mutant subgroups.
    explanation: >-
      The pooled cohort localizes the favorable outcome association to the bZIP
      in-frame-indel subgroup rather than every classification-included variant.
- name: Other CEBPA-Mutated AML
  display_name: CEBPA-mutated AML outside the bZIP in-frame-indel subgroup
  description: >-
    Residual analytic category containing somatic CEBPA mutation patterns other
    than an in-frame bZIP insertion/deletion, including isolated TAD mutations,
    bZIP stop/frameshift mutations, and bZIP missense mutations. This is not a
    separately grounded ontology entity, and membership does not imply exclusion
    from every formal classification: current ICC/ELN recommendations can include
    bZIP missense variants, while WHO membership is broader still. The pooled
    outcome evidence does not extend the indel-specific favorable signal to the
    entire residual group.
  genes:
  - preferred_term: CEBPA
    term:
      id: hgnc:1833
      label: CEBPA
  evidence:
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only bZIPInDel patients had significantly higher rates of complete
      remission and longer relapse free and overall survival (OS) compared with
      all other CEBPA-mutant subgroups.
    explanation: >-
      The pooled cohort separates bZIP in-frame insertion/deletion cases from
      other CEBPA-mutant patterns on outcome.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ELN2022 and ICC recommendations (including CEBPA bZIPms).
    explanation: Current formal recommendations can include bZIP missense variants even though the pooled favorable-outcome signal was indel-specific.
definitions:
- name: WHO-HAEM5 AML with CEBPA mutation definition
  definition_type: DIAGNOSTIC_CRITERIA
  scope: WHO Classification of Haematolymphoid Tumours, fifth edition
  description: >-
    WHO-HAEM5 recognizes AML with biallelic CEBPA mutation or a single mutation
    in the bZIP region and retains a minimum 20% blast threshold for this entity.
    The local MONDO scope adds the requirement that the relevant CEBPA lesion or
    lesions be somatic rather than a germline-predisposition 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: >-
      include biallelic (biCEBPA) as well as single mutations located in the
      basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA).
    explanation: WHO-HAEM5 states the qualifying CEBPA patterns.
  - 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: >-
      at least 20% blasts for diagnosis.
    explanation: WHO-HAEM5 retains the 20% blast threshold for AML with CEBPA mutation.
- name: ICC 2022 AML with in-frame bZIP CEBPA mutation definition
  definition_type: DIAGNOSTIC_CRITERIA
  scope: International Consensus Classification 2022
  description: >-
    ICC recognizes AML with an in-frame bZIP CEBPA mutation at a minimum of 10%
    blasts, irrespective of allelic state. Pooled analyses describe current ICC
    recommendations as including bZIP missense variants; that classification
    boundary must not be equated with the narrower indel-specific favorable
    outcome or generalized to every CEBPA-mutated AML case.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in-frame bZIP-mutation irrespective of double or single CEBPA-mutated
      status [12– 14] has been adapted in both ICC and the 2022 ELN
      recommendation
    explanation: The classification review describes the ICC shift to in-frame bZIP mutation irrespective of allelic state.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, ICC and ELN require a minimum of 10% blast for AML-CEBPA,
      whereas WHO-5 mandates 20% blast threshold.
    explanation: The review directly contrasts the ICC and WHO blast thresholds.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ELN2022 and ICC recommendations (including CEBPA bZIPms).
    explanation: The pooled analysis documents that current ICC/ELN recommendations can include bZIP missense variants.
mechanistic_hypotheses:
- hypothesis_group_id: cebpa_variant_convergence
  hypothesis_label: Variant-specific CEBPA dysfunction converges on differentiation arrest
  status: CANONICAL
  description: >-
    N-terminal truncating lesions preserve and overproduce p30, whereas
    C-terminal bZIP lesions alter DNA binding and dimerization. These distinct
    molecular defects converge on abnormal granulocytic transcription,
    differentiation arrest, leukemic progenitor expansion, and AML.
  evidence:
  - reference: PMID:11242107
    reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant proteins block wild-type C/EBPalpha DNA binding and
      transactivation of granulocyte target genes in a dominant-negative manner,
      and fails to induce granulocytic differentiation.
    explanation: Founding functional evidence connects human AML CEBPA mutations to dominant-negative differentiation failure.
- hypothesis_group_id: cebpa_high_risk_state
  hypothesis_label: Immune and mitochondrial expression state correlates with relapse risk
  status: EMERGING
  applies_to_subtypes:
  - CEBPA bZIP In-Frame-Indel AML
  description: >-
    A subset of bZIP in-frame-indel AML shows interferon-signaling and mitochondrial
    expression programs associated with shorter event-free survival. The data
    are prognostic correlations; the direction and causal intermediates remain
    unresolved.
  evidence:
  - reference: PMID:38253683
    reference_title: Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA-sequencing analysis revealed an enrichment of interferon (IFN)
      signaling and metabolic pathways in those with a shorter event-free
      survival (EFS).
    explanation: This supports association with outcome but not a causal pathway from CEBPA mutation to relapse.
pathophysiology:
- name: N-Terminal CEBPA p42-to-p30 Dysregulation
  description: >-
    Acquired N-terminal TAD frameshift or nonsense variants truncate the p42
    isoform while permitting downstream translation reinitiation and excess p30.
    The retained p30 protein interferes with normal C/EBPalpha transcriptional
    control; this is a dominant-negative isoform imbalance rather than simple
    absence of the protein.
  genes:
  - preferred_term: CEBPA
    term:
      id: hgnc:1833
      label: CEBPA
  gene_products:
  - preferred_term: CCAAT/enhancer binding protein alpha
    term:
      id: NCIT:C45488
      label: CCAAT/Enhancer Binding Protein Alpha
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    modifier: ABNORMAL
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  evidence:
  - reference: PMID:11242107
    reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that five mutations in the amino terminus truncate the
      full-length protein, but did not affect a 30-kD protein initiated further
      downstream.
    explanation: Human AML variants were shown to truncate p42 while preserving downstream p30 translation.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the aberrant dominant-negative p30 isoform from the second protein
      translation initiation codon and thus suppress myeloid differentiation
    explanation: The review states the isoform-specific consequence of N-terminal lesions.
  downstream:
  - target: Granulocytic Differentiation Arrest
    description: Excess p30 disrupts transcription of granulocytic target genes and blocks maturation.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11242107
      reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mutant proteins block wild-type C/EBPalpha DNA binding and
        transactivation of granulocyte target genes in a dominant-negative
        manner, and fails to induce granulocytic differentiation.
      explanation: Functional assays directly connect mutant CEBPA to failure of granulocytic differentiation.
  - target: Premalignant HSC and Leukemia-Initiating Progenitor Expansion
    description: Loss of p42-mediated control permits abnormal myeloid progenitor proliferation and leukemia initiation.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - p42 loss with retained p30 expression
    - loss of normal progenitor proliferation control
    evidence:
    - reference: PMID:18394553
      reference_title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        p42 was required for control of myeloid progenitor proliferation, and
        p42-deficient mice developed AML with complete penetrance.
      explanation: The p30-only mouse model links p42 loss to progenitor proliferation and AML.
- name: C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction
  description: >-
    Acquired C-terminal bZIP in-frame indels or missense variants alter the
    DNA-binding and leucine-zipper dimerization region. In-frame bZIP indels are
    the prognostically favorable mutation class, but they remain leukemogenic
    lesions that disturb CEBPA-regulated transcription and lineage commitment.
  genes:
  - preferred_term: CEBPA
    term:
      id: hgnc:1833
      label: CEBPA
  gene_products:
  - preferred_term: CCAAT/enhancer binding protein alpha
    term:
      id: NCIT:C45488
      label: CCAAT/Enhancer Binding Protein Alpha
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    modifier: ABNORMAL
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the C-terminal/bZIP in-frame indels or missense mutations disrupt protein
      dimerization and DNA binding.
    explanation: The full-text review states the bZIP functional consequence.
  downstream:
  - target: Granulocytic Differentiation Arrest
    description: Abnormal bZIP DNA binding and dimerization disrupt the CEBPA differentiation program.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1007/s11899-023-00699-3
      reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CEBPA function and downstream cellular processes such as cell cycle
        arrest and myeloid differentiation [16].
      explanation: The review connects bZIP-containing mutation patterns to impaired differentiation.
  - target: Premalignant HSC and Leukemia-Initiating Progenitor Expansion
    description: C-terminal lesions expand premalignant long-term HSCs before overt leukemia.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19878871
      reference_title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        C-terminal C/EBPalpha mutations increase the proliferation of long-term
        hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and
        override normal HSC homeostasis, leading to expansion of premalignant
        HSCs.
      explanation: Knock-in mice directly show the premalignant HSC effect of C-terminal lesions.
- name: Granulocytic Differentiation Arrest
  description: >-
    Variant-specific failure of CEBPA transcription prevents normal granulocytic
    maturation. Immature myeloid progenitors persist instead of completing the
    neutrophil differentiation program.
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: granulocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030851
      label: granulocyte differentiation
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:11242107
    reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ours is the first report of CEBPA mutations in human neoplasia, and such
      mutations are likely to induce the differentiation block found in AML.
    explanation: Human AML functional evidence identifies differentiation arrest as the consequence of CEBPA mutation.
  downstream:
  - target: Premalignant HSC and Leukemia-Initiating Progenitor Expansion
    description: Arrested progenitors provide the cellular substrate for self-renewal and leukemic initiation.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of terminal granulocytic maturation
    - persistence of committed myeloid progenitors
    evidence:
    - reference: PMID:19878871
      reference_title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        N-terminal C/EBPalpha mutations are silent with regards to HSC expansion,
        but allow the formation of committed myeloid progenitors, the templates
        for leukemia-initiating cells.
      explanation: The knock-in model identifies committed myeloid progenitors as leukemia-initiating templates.
- name: Premalignant HSC and Leukemia-Initiating Progenitor Expansion
  description: >-
    C-terminal lesions can expand premalignant long-term HSCs, while N-terminal
    lesions preserve committed myeloid progenitors that can become
    leukemia-initiating cells. Combined N- and C-terminal lesions incorporate
    both properties and accelerate disease development.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:19878871
    reference_title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The combination of N- and C-terminal C/EBPalpha mutations incorporates
      both features, accelerating disease development and explaining the
      clinical prevalence of this configuration of CEBPA mutations.
    explanation: The knock-in model demonstrates complementary cellular effects of the classic double-mutant pattern.
  downstream:
  - target: Leukemic Myeloblast Accumulation
    description: Expanded leukemia-initiating progenitors generate an overt myeloblast population.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - acquisition or selection of a leukemia-initiating clone
    evidence:
    - reference: PMID:18394553
      reference_title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population
        that gave rise only to myeloid cells in recipient mice.
      explanation: Transferable myeloid leukemia-initiating cells connect progenitor expansion to overt leukemia.
- name: Leukemic Myeloblast Accumulation
  description: >-
    Leukemic myeloblasts expand in bone marrow and may circulate in blood. This
    establishes the acute leukemic state and creates a marrow environment that
    suppresses normal downstream hematopoietic production.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  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: >-
      at least 20% blasts for diagnosis.
    explanation: WHO establishes an overt blast threshold for this genetic AML entity.
  downstream:
  - target: Leukemia
    description: Expansion of a clonal myeloid blast population constitutes the leukemia phenotype.
    hypothesis_groups:
    - cebpa_variant_convergence
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11242107
      reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we identify heterozygous mutations in CEBPA in ten patients with
        acute myeloid leukemia (AML).
      explanation: The founding human series directly associates acquired CEBPA mutations with AML.
  - target: Leukocytosis
    description: Circulating blast burden can produce an elevated total leukocyte count.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - release of leukemic blasts into peripheral blood
    evidence:
    - reference: PMID:34320176
      reference_title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical
        factors: they were significantly younger (median, 46 and 50 years,
        respectively) and had higher white blood cell (WBC) counts at diagnosis
      explanation: The large cohort directly supports higher diagnostic WBC counts in the major CEBPA-defined groups.
  - target: Suppression of Normal Hematopoiesis
    description: The leukemic marrow environment impedes production of downstream normal blood cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - inhibition of normal HSC-to-progenitor differentiation
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Rather, AML inhibits production of downstream hematopoietic cells by
        impeding differentiation at the HSC-progenitor transition.
      explanation: Human and xenograft data support differentiation-mediated suppression rather than simple HSC displacement.
- name: Suppression of Normal Hematopoiesis
  description: >-
    The AML marrow environment impedes normal differentiation downstream of the
    hematopoietic stem-cell compartment. Reduced erythroid, megakaryocytic, and
    granulocytic output produces multilineage or lineage-specific cytopenias.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AML inhibits production of downstream hematopoietic cells by impeding
      differentiation at the HSC-progenitor transition.
    explanation: Patient marrow analysis and xenografts support impaired normal downstream production.
  downstream:
  - target: Pancytopenia
    description: Multilineage suppression can reduce erythrocytes, platelets, and neutrophils together.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced erythroid, megakaryocytic, and granulocytic output
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute myeloid leukemia (AML) induces bone marrow (BM) failure in
        patients, predisposing them to life-threatening infections and bleeding.
      explanation: The source establishes AML marrow failure and cytopenic complications but does not quantify pancytopenia in this subtype.
  - target: Anemia
    description: Suppressed erythroid production lowers circulating red-cell mass.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced erythroid progenitor output
    evidence:
    - reference: DOI:10.1002/ajh.26822
      reference_title: "Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell
        cancer characterized by unbridled proliferation of malignant marrow stem
        cells with associated infection, anemia, and bleeding.
      explanation: This current AML review directly identifies anemia as a marrow-disease manifestation.
  - target: Thrombocytopenia
    description: Suppressed megakaryocytic output lowers the platelet count.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced megakaryocyte and platelet production
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        normal progenitors and other downstream hematopoietic cells were reduced
        following transplantation of primary AMLs
      explanation: The study supports reduced downstream cells broadly; the lineage-specific platelet inference is partial.
  - target: Neutropenia
    description: Suppressed granulocytic output lowers mature neutrophil production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced granulocytic progenitor output
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        normal progenitors and other downstream hematopoietic cells were reduced
        following transplantation of primary AMLs
      explanation: The study supports reduced downstream hematopoietic production; the neutrophil-specific inference is partial.
  - target: Cytopenia-Associated Complications
    description: Lineage-specific cytopenias lead to fatigue, bleeding, and infection susceptibility.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - anemia
    - thrombocytopenia
    - neutropenia
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute myeloid leukemia (AML) induces bone marrow (BM) failure in
        patients, predisposing them to life-threatening infections and bleeding.
      explanation: The source directly links AML marrow failure to infection and bleeding complications.
- name: Cytopenia-Associated Complications
  description: >-
    Anemia contributes to fatigue, thrombocytopenia produces bruising or
    bleeding, and neutropenia increases bacterial and fungal infection risk.
    These are AML-wide consequences rather than distinctive CEBPA-subtype
    features.
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  evidence:
  - reference: DOI:10.1002/ajh.26822
    reference_title: "Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell
      cancer characterized by unbridled proliferation of malignant marrow stem
      cells with associated infection, anemia, and bleeding.
    explanation: The review identifies the major cytopenia-associated AML complications.
  downstream:
  - target: Fatigue
    description: Anemia and systemic leukemia burden contribute to fatigue.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced oxygen-carrying capacity from anemia
    evidence:
    - reference: PMID:30131851
      reference_title: Patient-reported fatigue prior to treatment is prognostic of survival in patients with acute myeloid leukemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fatigue is one of the most commonly reported symptoms of AML.
      explanation: A prospective AML symptom study directly supports fatigue at presentation.
  - target: Abnormal Bleeding
    description: Reduced platelet production increases bruising and hemorrhage risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - thrombocytopenia
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute myeloid leukemia (AML) induces bone marrow (BM) failure in
        patients, predisposing them to life-threatening infections and bleeding.
      explanation: The source directly links AML marrow failure to bleeding.
  - target: Recurrent Infections
    description: Reduced mature neutrophil production increases susceptibility to severe infection.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neutropenia
    evidence:
    - reference: PMID:23901108
      reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute myeloid leukemia (AML) induces bone marrow (BM) failure in
        patients, predisposing them to life-threatening infections and bleeding.
      explanation: The source directly links AML marrow failure to life-threatening infection risk.
- name: Correlated IFN and Mitochondrial High-Risk State
  description: >-
    Within the CEBPA bZIP in-frame-indel analytic subgroup, a subset has
    increased interferon-stimulated and mitochondrial-complex gene expression
    associated with shorter
    event-free survival. This node is explicitly an emerging, correlation-based
    risk hypothesis rather than a settled causal CEBPA mechanism.
  subtypes:
  - CEBPA bZIP In-Frame-Indel AML
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:38253683
    reference_title: Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and
      ATP5IF1) were overexpressed and were associated with poorer survival
    explanation: The cohort supports a prognostic association, not causal direction.
  mechanism_confidence: PROVISIONAL
histopathology:
- name: Myeloblast Predominance
  finding_term:
    preferred_term: Myeloblasts present
    term:
      id: NCIT:C155995
      label: Myeloblasts Present
  diagnostic: true
  description: >-
    AML diagnosis is based on accumulation of myeloblasts in blood or bone marrow,
    with CEBPA mutation status defining this molecularly specified subtype.
  evidence:
  - reference: PMID:23590662
    reference_title: "Acute myeloid leukemia: advances in diagnosis and classification."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "myeloblasts in the blood or bone marrow."
    explanation: >-
      The abstract directly states that AML is characterized by myeloblasts in
      blood or bone marrow.
phenotypes:
- category: Hematologic
  name: Leukemia
  description: Clonal proliferation of leukemic myeloid blasts in blood and bone marrow.
  phenotype_term:
    preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  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: >-
      at least 20% blasts for diagnosis.
    explanation: >-
      WHO explicitly recognizes an AML entity defined by CEBPA mutation and an
      overt blast threshold.
- category: Hematologic
  name: Pancytopenia
  description: >-
    Combined anemia, thrombocytopenia, and neutropenia can result from marrow
    replacement and suppression of normal hematopoiesis.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rather, AML inhibits production of downstream hematopoietic cells by
      impeding differentiation at the HSC-progenitor transition.
    explanation: This supports multilineage cytopenia mechanistically but does not quantify pancytopenia in CEBPA-mutated AML.
- category: Hematologic
  name: Anemia
  description: Reduced erythrocyte mass from marrow failure and ineffective hematopoiesis.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: DOI:10.1002/ajh.26822
    reference_title: "Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell
      cancer characterized by unbridled proliferation of malignant marrow stem
      cells with associated infection, anemia, and bleeding.
    explanation: The AML review directly identifies anemia as a clinical manifestation.
- category: Hematologic
  name: Thrombocytopenia
  description: Reduced platelet production contributes to bruising and bleeding.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal progenitors and other downstream hematopoietic cells were reduced
      following transplantation of primary AMLs
    explanation: Reduced downstream hematopoietic production supports thrombocytopenia indirectly; no CEBPA-specific frequency is inferred.
- category: Hematologic
  name: Neutropenia
  description: >-
    Reduced mature neutrophil output from marrow failure increases risk of severe
    bacterial and fungal infection.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal progenitors and other downstream hematopoietic cells were reduced
      following transplantation of primary AMLs
    explanation: Reduced downstream hematopoietic production supports neutropenia indirectly; no CEBPA-specific frequency is inferred.
- category: Hematologic
  name: Leukocytosis
  description: >-
    Some patients have elevated circulating leukemic blast burden and increased
    total leukocyte count.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  context: Enriched in biallelic and single-bZIP CEBPA groups but not obligatory.
  evidence:
  - reference: PMID:34320176
    reference_title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors:
      they were significantly younger (median, 46 and 50 years, respectively)
      and had higher white blood cell (WBC) counts at diagnosis
    explanation: This large cohort directly supports higher diagnostic WBC counts in the main CEBPA-defined groups.
- category: Bleeding
  name: Abnormal Bleeding
  description: >-
    Bleeding, easy bruising, petechiae, or mucosal hemorrhage can occur from
    thrombocytopenia.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients,
      predisposing them to life-threatening infections and bleeding.
    explanation: The study directly links AML marrow failure to bleeding risk.
- category: Infectious
  name: Recurrent Infections
  description: >-
    Infection susceptibility reflects neutropenia and dysfunctional hematopoiesis
    during AML presentation or therapy.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  context: Infection susceptibility is AML-wide; recurrence frequency is not established specifically for this subtype.
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients,
      predisposing them to life-threatening infections and bleeding.
    explanation: The study supports infection susceptibility, while the HPO term's recurrent wording is broader than the source.
- category: Constitutional
  name: Fatigue
  description: Fatigue is a nonspecific symptom of anemia and systemic leukemia burden.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:30131851
    reference_title: Patient-reported fatigue prior to treatment is prognostic of survival in patients with acute myeloid leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fatigue is one of the most commonly reported symptoms of AML.
    explanation: A prospective untreated-AML cohort directly supports fatigue as a common presenting symptom.
genetic:
- name: CEBPA
  gene_term:
    preferred_term: CEBPA
    term:
      id: hgnc:1833
      label: CEBPA
  association: Somatic driver mutation defining AML-CEBPA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  case_fractions:
  - population: Adults with AML recruited to Study Alliance Leukemia trials
    case_fraction_percent: 5.1
    cohort_size: 4708
    notes: >-
      This is the fraction of an adult AML trial cohort with any CEBPA mutation,
      not population prevalence and not the frequency of the narrower bZIP
      in-frame-indel subgroup.
    evidence:
    - reference: PMID:34320176
      reference_title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and
        109 CEBPAsm
      explanation: >-
        The denominator-defined adult AML cohort establishes a cohort-specific
        CEBPA-mutated case fraction without implying general-population prevalence.
  evidence:
  - reference: PMID:37261703
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the
      common genetic alterations in acute myeloid leukemia (AML), which can be
      associated with sporadic and familial AML.
    explanation: >-
      This review supports CEBPA mutation as a recurrent genetic alteration in
      AML and frames the sporadic/familial distinction.
  variants:
  - name: N-terminal CEBPA truncating mutation with retained p30 translation
    description: >-
      Somatic N-terminal TAD frameshift or nonsense variants truncate p42 while
      preserving downstream p30 translation, producing a dominant-negative
      isoform imbalance and impaired granulocytic transcription.
    gene:
      preferred_term: CEBPA
      term:
        id: hgnc:1833
        label: CEBPA
    type: truncating_variant
    functional_effects:
    - function: CEBPA transcriptional regulation of granulocytic differentiation
      description: Loss of p42 with retained p30 blocks wild-type DNA binding and transactivation.
      type: dominant-negative isoform imbalance
    evidence:
    - reference: PMID:11242107
      reference_title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        five mutations in the amino terminus truncate the full-length protein,
        but did not affect a 30-kD protein initiated further downstream.
      explanation: Functional human AML evidence establishes the p42-truncation/p30-retention pattern.
  - name: C-terminal CEBPA bZIP in-frame insertion-deletion
    description: >-
      Somatic in-frame insertions or deletions in the C-terminal bZIP region
      disrupt DNA binding and dimerization. This variant class, rather than all
      CEBPA variants, carries the reproducible favorable-risk association.
    gene:
      preferred_term: CEBPA
      term:
        id: hgnc:1833
        label: CEBPA
    type: inframe_indel
    functional_effects:
    - function: CEBPA DNA binding and dimerization
      description: bZIP structural alteration disrupts DNA binding and protein dimerization.
      type: altered transcription-factor function
    evidence:
    - reference: PMID:34320176
      reference_title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the clinical and molecular features as well as the favorable survival
        were confined to patients with in-frame mutations in bZIP
        (CEBPAbZIP-inf).
      explanation: The large cohort identifies the bZIP in-frame class as the outcome-defining variant pattern.
  notes: >-
    This disease entry focuses on somatic CEBPA-mutated AML. Persistent CEBPA
    variants during remission or clinical family history should prompt
    evaluation for germline CEBPA predisposition, which is a separate hereditary
    AML context.
- name: WT1
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  association: Cohort-dependent prognostic co-mutation in CEBPA bZIP in-frame-indel AML
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  subtype: CEBPA bZIP In-Frame-Indel AML
  evidence:
  - reference: PMID:38253683
    reference_title: Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent WT1 or DNMT3A mutations significantly predicted worse survival
      in AML patients with CEBPAbZIP-inf.
    explanation: This cohort found an adverse WT1 association, supporting one side of a conflicting literature.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as
      ELN2022 adverse risk aberrations) had no independent impact on OS
    explanation: A larger pooled analysis did not find an independent OS effect, so WT1 is not encoded as a settled transplant trigger.
  review_notes: Prognostic effect is cohort-dependent and should not override integrated AML risk or MRD by itself.
- name: DNMT3A
  gene_term:
    preferred_term: DNMT3A
    term:
      id: hgnc:2978
      label: DNMT3A
  association: Reported adverse prognostic co-mutation with unresolved replication
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  subtype: CEBPA bZIP In-Frame-Indel AML
  evidence:
  - reference: PMID:38253683
    reference_title: Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent WT1 or DNMT3A mutations significantly predicted worse survival
      in AML patients with CEBPAbZIP-inf.
    explanation: This cohort supports an adverse association, but it does not establish a universal independent effect.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      results are likely attributable to the small sample sizes limiting the
      analysis power.
    explanation: The review explicitly characterizes co-mutation prognostic results as controversial.
  review_notes: Do not treat DNMT3A alone as a validated indication for transplant in first remission.
- name: FLT3-ITD
  gene_term:
    preferred_term: FLT3
    term:
      id: hgnc:3765
      label: FLT3
  association: Cohort-dependent adverse prognostic co-mutation in some CEBPA-mutated AML contexts
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  subtype: CEBPA bZIP In-Frame-Indel AML
  variants:
  - name: FLT3 internal tandem duplication
    description: Somatic FLT3 internal tandem duplication reported as an adverse marker in some CEBPA-mutated cohorts.
    gene:
      preferred_term: FLT3
      term:
        id: hgnc:3765
        label: FLT3
    type: internal_tandem_duplication
    evidence:
    - reference: PMID:36701843
      reference_title: Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: FLT3-ITDpos was associated with worse outcomes.
      explanation: The normal-karyotype cohort reports the adverse FLT3-ITD association.
  evidence:
  - reference: PMID:36701843
    reference_title: Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For relapse-free survival (RFS) and cumulative incidence of relapse,
      bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes;
      FLT3-ITDpos was associated with worse outcomes.
    explanation: This human cohort supports adverse association in one normal-karyotype setting.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as
      ELN2022 adverse risk aberrations) had no independent impact on OS
    explanation: The pooled analysis did not reproduce an independent OS effect, establishing uncertainty.
  review_notes: Interpret with integrated AML genetics, treatment context, and MRD rather than as an isolated transplant trigger.
progression:
- phase: Diagnosis and Classification Assignment
  notes: >-
    Establish AML, apply the selected WHO or ICC blast threshold, identify the
    precise CEBPA domain and variant type, and distinguish disease definition
    from ELN treatment-context risk assignment. Diagnostic marrow VAF cannot by
    itself establish somatic origin.
  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: >-
      include biallelic (biCEBPA) as well as single mutations located in the
      basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA).
    explanation: WHO shows why exact mutation pattern is part of disease assignment.
- phase: Induction and Complete Remission
  subtype: CEBPA bZIP In-Frame-Indel AML
  notes: >-
    Fit patients usually receive intensive induction. The bZIP in-frame-indel
    subgroup has higher complete-remission rates and better survival than other
    CEBPA mutation patterns, but this prognostic association does not eliminate
    relapse risk.
  evidence:
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only bZIPInDel patients had significantly higher rates of complete
      remission and longer relapse free and overall survival (OS) compared with
      all other CEBPA-mutant subgroups.
    explanation: The pooled analysis identifies the response and survival advantage of the in-frame bZIP subgroup.
- phase: Consolidation and MRD Reassessment
  notes: >-
    Bone-marrow multiparameter-flow MRD during consolidation refines relapse
    risk. CEBPA mutation detection is not automatically an MRD assay because a
    persisting variant can indicate germline predisposition; interpret molecular
    findings with remission tissue and broader clonality context.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MRD-positive status during consolidation but not after induction was
      associated with an increased risk of relapse and decreased relapse free
      survival.
    explanation: The CEBPA review summarizes the prognostic timing of flow-cytometric MRD.
  - reference: PMID:41397238
    reference_title: "2025 update on MRD in acute myeloid leukemia: a consensus document from the ELN-DAVID MRD Working Party."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Measurable residual disease (MRD) monitoring has become a critical
      component in the management of acute myeloid leukemia (AML), to inform
      prognosis, guide therapy, and serve as a key end point in clinical trials.
    explanation: Current ELN-DAVID consensus establishes MRD as a dynamic AML management tool.
- phase: Relapsed or Refractory Disease
  notes: >-
    Relapsed CEBPA double-mutated AML can remain chemotherapy-sensitive.
    Reinduction, molecular reassessment, MRD response, donor suitability, and
    overall AML risk inform allogeneic transplantation in second remission or
    refractory disease.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The second CR rate was reported to be 83–85% [78, 79].
    explanation: The review supports retained chemosensitivity after relapse in double-mutated disease.
diagnosis:
- name: Complete Blood Count and Peripheral Blood Smear
  diagnosis_term:
    preferred_term: complete blood count
    term:
      id: NCIT:C28133
      label: Blood Cell Count
  description: >-
    CBC and smear assess anemia, thrombocytopenia, neutropenia or leukocytosis
    and identify circulating blasts. The pattern establishes urgency and
    supports AML evaluation but is not specific for CEBPA-mutated disease.
  results: Cytopenias or leukocytosis with circulating myeloblasts may be present.
  evidence:
  - reference: PMID:34320176
    reference_title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors:
      they were significantly younger (median, 46 and 50 years, respectively)
      and had higher white blood cell (WBC) counts at diagnosis
    explanation: The cohort supports CBC-detectable WBC elevation in major CEBPA-defined groups.
- name: Bone Marrow Morphology and Blast Enumeration
  diagnosis_term:
    preferred_term: biopsy of bone marrow
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  description: >-
    Aspirate and core biopsy establish an acute myeloid blast process, assess
    maturation and dysplasia, and supply material for flow, cytogenetic, and
    molecular studies. Apply the classification-specific threshold: WHO-HAEM5
    requires at least 20% blasts for AML with CEBPA mutation, whereas ICC uses
    at least 10% for its in-frame bZIP entity.
  results: An acute myeloid blast proliferation meeting the selected WHO or ICC threshold.
  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: >-
      at least 20% blasts for diagnosis.
    explanation: WHO directly establishes the CEBPA-entity blast threshold.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ICC and ELN require a minimum of 10% blast for AML-CEBPA, whereas WHO-5
      mandates 20% blast threshold.
    explanation: The classification review states the ICC-versus-WHO threshold difference.
- name: Flow-Cytometric Myeloid Lineage Assessment
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: >-
    Multiparameter flow cytometry confirms an acute myeloid immunophenotype and
    establishes a leukemia-associated phenotype for later MRD assessment.
    CEBPA double-mutated blasts frequently express CD7, CD15, and HLA-DR, but no
    immunophenotype substitutes for sequencing.
  results: Myeloid blasts with a reproducible leukemia-associated immunophenotype.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      frequency of CD7, CD15, and HLA-DR expression
    explanation: The review summarizes the characteristic but non-pathognomonic flow phenotype.
- name: Cytogenetic and Broad Myeloid Molecular Profiling
  diagnosis_term:
    preferred_term: cytogenetic analysis
    term:
      id: NCIT:C18280
      label: Cytogenetic Analysis
  description: >-
    Karyotyping/FISH and broad myeloid NGS identify competing AML-defining
    lesions, myelodysplasia-related abnormalities, and co-mutations that affect
    integrated risk. A normal karyotype is common but is not a diagnostic
    requirement.
  results: Cytogenetic and co-mutation profile used for diagnostic hierarchy and risk assignment.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CEBPAdm is strongly associated with a normal karyotype
    explanation: The review supports cytogenetic assessment while showing that CEBPA AML is often karyotypically normal.
- name: Full-Length CEBPA Sequencing and Variant Annotation
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Sequence the full single-exon CEBPA coding region and report domain,
    insertion/deletion frame, variant allele fraction, and co-occurring CEBPA
    lesions. Capture-based NGS is preferred over amplicon-only methods because
    the locus is GC-rich and indel-heavy. Routine short reads may not phase
    distant N- and C-terminal variants.
  results: Precise CEBPA mutation pattern supporting WHO/ICC assignment and ELN risk classification.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      method for CEBPA mutation detection is full length sequencing of this
      single exon gene.
    explanation: The review directly recommends full-length sequencing.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Capture-based NGS has been shown to perform better than amplicon-based NGS
      in CEBPA mutation detection
    explanation: This supports the assay-design recommendation for the GC-rich, indel-prone locus.
- name: Constitutional Evaluation for Germline CEBPA Predisposition
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Evaluate germline predisposition when the CEBPA variant persists in complete
    remission, onset or family history is suggestive, or donor selection makes
    constitutional status consequential. Marrow or blood VAF near 50% cannot
    distinguish germline from somatic disease. Cultured skin fibroblasts are the
    preferred constitutional specimen; related donors require appropriate
    testing and counseling.
  results: Constitutional testing distinguishes this somatic-only entry from germline CEBPA-associated predisposition.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VAF cannot be reliably used as a marker
    explanation: This directly refutes using diagnostic blood or marrow VAF alone to assign origin.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The gold standard constitutional sample type for germline confirmation is
      cultured skin fibroblasts
    explanation: The review identifies the preferred constitutional specimen.
- name: Bone-Marrow Multiparameter Flow MRD Assessment
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: >-
    Assess MRD using bone-marrow multiparameter flow after therapy, especially
    during consolidation, and interpret it with integrated genetic risk.
    Persisting CEBPA sequence alone is not automatically residual leukemia
    because it can indicate a constitutional variant.
  results: MRD category used for dynamic relapse-risk and transplant assessment.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MRD-positive status during consolidation but not after induction was
      associated with an increased risk of relapse and decreased relapse free
      survival.
    explanation: The CEBPA review supports consolidation-time MFC-MRD as prognostic.
  - reference: PMID:41397238
    reference_title: "2025 update on MRD in acute myeloid leukemia: a consensus document from the ELN-DAVID MRD Working Party."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MRD recommendations are tailored to individual prognostic and genetic
      subgroups.
    explanation: Current ELN-DAVID consensus supports genotype-aware MRD interpretation.
differential_diagnoses:
- name: Germline CEBPA-Associated Myeloid Neoplasm Predisposition
  description: >-
    Familial or de novo constitutional CEBPA pathogenic variants can produce AML
    with a second acquired CEBPA lesion and can closely resemble sporadic
    double-mutated disease.
  distinguishing_features:
  - Persistence of a CEBPA variant in complete remission supports constitutional evaluation.
  - Diagnostic blood or marrow VAF near 50% is not sufficient to distinguish origin.
  - Cultured skin fibroblast testing, family evaluation, and genetic counseling establish constitutional status.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the persistence of a CEBPA mutation at the time of complete remission
      warrants
    explanation: Persistence in remission is a direct trigger for germline evaluation even without family history.
- name: Acute Myeloid Leukemia with Mutated NPM1
  disease_term:
    preferred_term: acute myeloid leukemia with mutated NPM1
    term:
      id: MONDO:0044923
      label: acute myeloid leukemia with mutated NPM1
  description: A separate mutation-defined AML entity that may present with similar acute myeloid morphology.
  distinguishing_features:
  - A defining NPM1 mutation and application of the WHO/ICC diagnostic hierarchy distinguish this entity.
  - NPM1 co-mutation is uncommon in the biallelic and single-bZIP CEBPA groups.
  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: include AML with NPM1 and AML with CEBPA mutation.
    explanation: WHO lists NPM1-mutated and CEBPA-mutated AML as separate mutation-defined types.
- name: Acute Promyelocytic Leukemia with PML::RARA
  disease_term:
    preferred_term: acute promyelocytic leukemia
    term:
      id: MONDO:0012883
      label: acute promyelocytic leukemia
  description: A genetically defined AML emergency that can overlap in cytopenic acute-leukemia presentation.
  distinguishing_features:
  - Promyelocytic morphology, coagulopathy, and PML::RARA testing distinguish APL and require immediate disease-specific management.
  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: >-
      criteria for AML with PML::RARA, AML with RUNX1::RUNX1T1, and AML with
      CBF::MYH11
    explanation: WHO recognizes these as distinct AML types requiring lesion-specific assignment.
- name: Core-Binding-Factor Acute Myeloid Leukemia
  description: RUNX1::RUNX1T1- or CBFB::MYH11-defined AML can share an acute myeloid blast presentation.
  distinguishing_features:
  - Fusion testing identifies a core-binding-factor lesion and redirects classification and risk assessment.
  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: >-
      Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion
      Acute myeloid leukaemia with CBFB::MYH11 fusion
    explanation: WHO lists the two core-binding-factor AML types separately.
- name: Myelodysplastic Syndrome or ICC MDS/AML
  disease_term:
    preferred_term: myelodysplastic syndrome
    term:
      id: MONDO:0018881
      label: myelodysplastic syndrome
  description: Cytopenia, dysplasia, and 10-19% blasts can overlap at the MDS/AML boundary.
  distinguishing_features:
  - Apply the selected classification's blast threshold and CEBPA mutation-pattern requirements.
  - WHO retains 20% blasts for AML with CEBPA mutation, whereas ICC permits its in-frame bZIP entity from 10% blasts.
  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: retaining a 20% blast cutoff to delineate MDS from AML.
    explanation: WHO describes the retained general boundary that must be reconciled with genetic-entity exceptions.
- name: AML with Myelodysplasia-Related Genetics
  description: >-
    Myelodysplasia-related cytogenetic or molecular abnormalities and prior MDS
    can coexist with a CEBPA mutation. Classification and risk assignment depend
    on the exact lesions and the selected WHO or ICC hierarchy; this entry does
    not assert a universal precedence rule.
  distinguishing_features:
  - Prior myeloid disease, myelodysplasia-related cytogenetics, and defining MR-gene mutations support AML-MR.
  - Broad NGS and cytogenetics are required because an incidental or nonqualifying CEBPA variant must not obscure independently qualifying AML-MR features.
  - Apply the selected framework's hierarchy rather than assuming that either label always supersedes the other.
  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: >-
      removal of morphology alone as a diagnostic premise to make a diagnosis
      of AML-MR;
    explanation: WHO-HAEM5 explicitly removes morphology alone as a sufficient basis for AML-MR.
- name: Mixed-Phenotype Acute Leukemia
  description: Acute leukemia of ambiguous lineage can overlap when blasts express cross-lineage markers.
  distinguishing_features:
  - Formal lineage criteria and flow/cytochemical evidence of more than one lineage distinguish MPAL.
  - A CEBPA mutation alone does not replace lineage assignment.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Mixed-phenotype acute leukaemia, B/myeloid
    explanation: WHO-HAEM5 recognizes MPAL as a separate ambiguous-lineage category.
treatments:
- name: Intensive Anthracycline- and Cytarabine-Based Chemotherapy
  description: >-
    Medically fit patients are generally treated with anthracycline- and
    cytarabine-based induction followed by cytarabine-containing consolidation.
    This is an AML treatment backbone, not a CEBPA-directed therapy. The favorable
    reproducible favorable-outcome evidence applies most securely to bZIP
    in-frame-indel disease treated intensively; it does not establish that every
    classification-included bZIP variant responds equivalently.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
    - preferred_term: daunorubicin
      term:
        id: CHEBI:41977
        label: daunorubicin
  target_mechanisms:
  - target: Leukemic Myeloblast Accumulation
    treatment_effect: INHIBITS
    description: Cytotoxic induction and consolidation reduce the proliferating leukemic blast population.
    evidence:
    - reference: DOI:10.1007/s11899-023-00699-3
      reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The anthracycline and cytarabine based induction chemotherapy followed
        by consolidation
      explanation: The CEBPA-focused review identifies intensive induction and consolidation as the principal treatment backbone for fit patients.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The anthracycline and cytarabine based induction chemotherapy followed by
      consolidation
    explanation: >-
      This supports the standard intensive AML backbone without treating an
      unreported trial result as efficacy evidence.
- name: Hypomethylating Agent Plus Venetoclax for Intensive-Therapy-Ineligible Patients
  description: >-
    A hypomethylating agent plus venetoclax is a lower-intensity frontline AML
    option when age, frailty, or comorbidity precludes intensive chemotherapy.
    CEBPA-specific evidence is limited: favorable-risk AML was excluded from
    VIALE-A, and the reported CEBPA double-mutated experience is a small subset.
    The addition of low-dose cytarabine is being studied and is not encoded as
    established standard care for this molecular subtype.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: venetoclax
      term:
        id: CHEBI:133021
        label: venetoclax
    - preferred_term: azacitidine
      term:
        id: NCIT:C288
        label: Azacitidine
  target_mechanisms:
  - target: Leukemic Myeloblast Accumulation
    treatment_effect: INHIBITS
    description: The combination is used to reduce the leukemic blast population in patients unable to receive intensive induction.
    evidence:
    - reference: DOI:10.1007/s11899-023-00699-3
      reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Recently, hypomethylating agents (HMA) coupled with venetoclax have been
        adapted as frontline therapy for patients who are not eligible for high
        intensity chemotherapy
      explanation: The review supports use of the lower-intensity combination to treat the leukemic disease in intensive-therapy-ineligible patients.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recently, hypomethylating agents (HMA) coupled with venetoclax have been
      adapted as frontline therapy for patients who are not eligible for high
      intensity chemotherapy
    explanation: The review supports this as an eligibility-based lower-intensity AML approach.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The complete remission (CR) and complete remission with incomplete count
      recovery (CRi) rate in this patient population were 75%.
    explanation: A small reported CEBPA double-mutated subset supports activity but cannot establish subtype-specific comparative efficacy.
  review_notes: >-
    No approved drug directly targets mutant CEBPA. NCT07451912 is testing a
    venetoclax/HMA/low-dose-cytarabine triplet and has no posted efficacy results.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    Retrospective double-mutated CEBPA cohorts found improved relapse-free but
    not overall survival from transplantation in first complete remission and
    support reserving allogeneic transplantation for refractory disease, relapse,
    or second remission. Whether co-mutations or post-treatment MRD identify a
    first-remission subgroup with an overall-survival benefit remains unresolved
    and is represented below as an open discussion, not a recommendation.
    Suspected germline CEBPA predisposition requires constitutional evaluation
    before related-donor selection.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Leukemic Myeloblast Accumulation
    treatment_effect: INHIBITS
    description: Conditioning and donor hematopoiesis provide cytoreduction and a graft-versus-leukemia effect in selected high-risk or relapsed settings.
    evidence:
    - reference: DOI:10.1007/s11899-023-00699-3
      reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This study provided evidence to reserve hematopoietic stem cell
        transplant to CR2 or refractory disease.
      explanation: The review supports transplant as an anti-leukemia strategy in selected later or refractory settings.
  evidence:
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While both autologous and allogeneic stem cell transplant provide improved
      RFS in CR1, the OS was not different compared to patient who received
      chemotherapy only. This study provided evidence to reserve hematopoietic
      stem cell transplant to CR2 or refractory disease.
    explanation: >-
      The review supports a limited CR1 role and later transplant use rather than
      routine upfront transplantation for favorable-risk disease.
  - reference: DOI:10.1007/s11899-023-00699-3
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This information is important for patient management including allogeneic
      stem cell transplant donor selection as well as patient family consultation
      and surveillance.
    explanation: Germline-versus-somatic assignment is clinically consequential for donor selection.
  review_notes: >-
    NCT06458257 is a recruiting observational study with no posted results; it
    does not establish benefit from transplantation in first remission.
- name: Supportive Care for Cytopenias and Infection Risk
  description: >-
    Supportive management includes red-cell and platelet transfusion when
    clinically indicated, prompt evaluation and treatment of infection, and
    individualized measures for disease- and therapy-associated cytopenias.
    These measures treat complications but do not eradicate the CEBPA-mutant clone.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  - preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:23901108
    reference_title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients,
      predisposing them to life-threatening infections and bleeding.
    explanation: Human AML marrow failure establishes the complications that supportive care addresses.
  - reference: PMID:34307165
    reference_title: "Improving Outcomes of Chemotherapy: Established and Novel Options for Myeloprotection in the COVID-19 Era."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      chemotherapy-induced myelosuppression is managed with chemotherapy dose
      delays/reductions and lineage-specific supportive care interventions, such
      as hematopoietic growth factors and blood transfusions.
    explanation: This oncology supportive-care review directly supports transfusion and lineage-specific management of treatment-associated myelosuppression.
disease_term:
  preferred_term: acute myeloid leukemia with CEBPA somatic mutations
  term:
    id: MONDO:0017894
    label: acute myeloid leukemia with CEBPA somatic mutations
clinical_trials:
- name: NCT06458257
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Recruiting observational study evaluating outcomes after allogeneic
    transplantation following induction and consolidation in newly diagnosed
    patients labeled high-relapse-risk CEBPA-mutant AML. It is not randomized
    and has no posted results, so efficacy is not established.
  evidence:
  - reference: clinicaltrials:NCT06458257
    reference_title: The Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Newly Diagnosed High-relapse-risk CEBPA Mutant Acute Myeloid Leukemia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To access whether the therapeutic regimen is effective for
      high-relapse-risk CEBPA mutant acute myeloid leukemia, the
      disease-free-survival (DFS), overall survival (OS), non-relapse-mortality
      of patients is evaluated.
    explanation: >-
      The registry states the planned outcomes; it does not provide an efficacy result.
  review_notes: >-
    ClinicalTrials.gov status checked 2026-07-17. The eligibility text is
    internally inconsistent about CD7, so CD7 is not encoded as a validated
    transplant-selection marker.
- name: NCT06529250
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Recruiting open-label randomized study comparing intermediate-dose HAD with
    a conventional regimen in CEBPA-mutated AML. The registry reports no results;
    superiority remains a study hypothesis.
  evidence:
  - reference: clinicaltrials:NCT06529250
    reference_title: "A Multicenter, Randomized, Controlled Clinical Trial of Intermediate-dose HAD Regimen for CEBPA Double-mutated Acute Myeloid Leukemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, this project intends to confirm the efficacy of
      intermediate-dose HAD in the treatment of CEBPA double-mutated AML is
      superior to the conventional treatment regimen through the multi-center RCT
      study.
    explanation: >-
      The trial summary describes the intended randomized comparison, not a completed result.
  review_notes: >-
    ClinicalTrials.gov status checked 2026-07-17. The title uses double-mutated
    CEBPA while current eligibility language refers to bZIP mutation, so the
    enrolled molecular population should be verified before interpreting results.
- name: NCT04415008
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Active-not-recruiting prospective multicenter single-arm phase 2 study of
    HAD induction with intensified cytarabine in newly diagnosed CEBPA
    double-mutated AML. No results are posted in the registry.
  evidence:
  - reference: clinicaltrials:NCT04415008
    reference_title: "A Prospective, Multicenter, Single Arm Clinical Study to Evaluate Efficacy of HAD Induction With Intensified Cytarabine in Newly-diagnosed CEBPA Double Mutated Acute Myeloid Leukemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HAD(homoharringtonine(HHT)+cytarabine+daunorubicin) with intermediate
      dose cytarabine improved the survival of AML, especially in patients with
      CEBPA double mutation.
    explanation: >-
      The registry text supplies the study rationale; the single-arm study has not posted results.
  review_notes: ClinicalTrials.gov status checked 2026-07-17; efficacy remains unreported.
- name: NCT07451912
  status: RECRUITING
  description: >-
    Recruiting open-label single-arm phase 1/2 study of venetoclax plus a
    hypomethylating agent and low-dose subcutaneous cytarabine for adults with
    newly diagnosed CEBPA-mutated AML who cannot tolerate intensive chemotherapy.
    It has no posted results and the triplet remains investigational.
  evidence:
  - reference: clinicaltrials:NCT07451912
    reference_title: Prospective Multicenter Clinical Study of Venetoclax Combined With Hypomethylating Agents and Subcutaneous Cytarabine in Induction Therapy for CEBPA-Mutated Acute Myeloid Leukemia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this clinical trial is to learn if a treatment
      combination-venetoclax plus hypomethylating agents (like azacitidine or
      decitabine) and low-dose cytarabine-works to treat adults with newly
      diagnosed CEBPA-mutated acute myeloid leukemia (AML) who can't tolerate
      intensive chemotherapy.
    explanation: The registry defines the investigational triplet and intensive-therapy-ineligible study population.
  review_notes: >-
    ClinicalTrials.gov status checked 2026-07-17. The registry labels this a
    combined phase 1/2 study; the phase field is omitted because the schema has
    no combined-phase value.
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
animal_models:
- species: Mus musculus
  genotype: Cebpa p30-only knock-in with loss of the p42 isoform
  description: >-
    A p30-only knock-in models the N-terminal human mutation consequence by
    removing p42 while retaining p30. Mice develop AML with complete penetrance
    and yield transplantable committed myeloid leukemia-initiating cells. The
    model isolates isoform imbalance and does not reproduce the common paired
    N-terminal plus bZIP genotype or the full human co-mutation landscape.
  genes:
  - preferred_term: Cebpa
    term:
      id: hgnc:1833
      label: CEBPA
  evidence:
  - reference: PMID:18394553
    reference_title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we modified the mouse Cebpa locus to express only p30. p30 supported the
      formation of granulocyte-macrophage progenitors. However, p42 was required
      for control of myeloid progenitor proliferation, and p42-deficient mice
      developed AML with complete penetrance.
    explanation: The engineered model directly tests the p42-loss/p30-retention mechanism and develops AML.
- species: Mus musculus
  genotype: Combined N-terminal and C-terminal Cebpa knock-in mutations
  description: >-
    Complementary Cebpa knock-in alleles model the classic paired mutation
    architecture. C-terminal lesions expand premalignant long-term HSCs, while
    N-terminal lesions allow committed myeloid leukemia-initiating progenitors;
    the combined genotype accelerates disease. Exact alleles and treatment
    context still differ from the heterogeneous human bZIP in-frame entity.
  genes:
  - preferred_term: Cebpa
    term:
      id: hgnc:1833
      label: CEBPA
  evidence:
  - reference: PMID:19878871
    reference_title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The combination of N- and C-terminal C/EBPalpha mutations incorporates
      both features, accelerating disease development and explaining the
      clinical prevalence of this configuration of CEBPA mutations.
    explanation: The paired knock-in experiment demonstrates complementary mutation effects and accelerated leukemogenesis.
- species: Danio rerio
  genotype: cebpa loss-of-function and N-terminal zP30-expressing mutants
  description: >-
    Zebrafish cebpa mutants resolve developmental HSPC generation and isoform
    function. N-terminal zP30 mutants impair myeloid differentiation without
    reducing HSPC number. This is a developmental hematopoiesis model, not an AML
    model, and it should not be used as evidence of leukemia penetrance or therapy.
  evidence:
  - reference: PMID:39500381
    reference_title: Cebpa is required for haematopoietic stem and progenitor cell generation and maintenance in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      while myeloid differentiation was impaired in cebpa N-terminal mutants
      expressing the truncated zP30 protein, the number of HSPCs was not affected
    explanation: The developmental model separates an N-terminal isoform effect on myeloid differentiation from HSPC abundance.
discussions:
- discussion_id: controversy_cebpa_classification_and_risk_boundaries
  prompt: >-
    How should WHO-HAEM5, ICC 2022, and ELN 2022 CEBPA categories be represented
    without conflating disease definition, blast threshold, allelic state, and
    treatment-context risk?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - definitions#WHO-HAEM5 AML with CEBPA mutation definition
  - definitions#ICC 2022 AML with in-frame bZIP CEBPA mutation definition
  - has_subtypes#CEBPA bZIP In-Frame-Indel AML
  rationale: >-
    WHO includes biallelic CEBPA or a single bZIP mutation and retains 20% blasts;
    ICC requires an in-frame bZIP mutation and permits diagnosis from 10% blasts;
    ELN assigns in-frame bZIP CEBPA to favorable risk in intensively treated
    adults. These are overlapping but non-identical assertions, and newer outcome
    data suggest that in-frame bZIP indels, not every bZIP mutation, carry the
    clearest favorable signal.
  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: >-
      include biallelic (biCEBPA) as well as single mutations located in the
      basic leucine zipper (bZIP) region of the gene (smbZIP- CEBPA).
    explanation: WHO-HAEM5 documents one diagnostic boundary.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only bZIPInDel patients had significantly higher rates of complete
      remission and longer relapse free and overall survival (OS) compared with
      all other CEBPA-mutant subgroups.
    explanation: Pooled outcome data sharpen the favorable signal to bZIP in-frame insertion/deletion cases.
  proposed_experiments:
  - experiment_id: exp_cebpa_harmonized_classification_outcomes
    name: Harmonized WHO-ICC-ELN prospective outcome analysis
    description: >-
      Prospectively phase full-length CEBPA variants and assign each case in
      parallel under WHO, ICC, and ELN rules, stratified by intensive versus
      lower-intensity treatment and serial flow MRD.
    decision_criterion: >-
      A boundary is clinically coherent if it independently separates remission,
      relapse-free survival, and overall survival after adjustment for treatment,
      age, co-mutations, and MRD in external validation cohorts.
- discussion_id: controversy_cebpa_comutations_mrd_and_transplant
  prompt: >-
    Which co-mutations or post-treatment MRD states identify in-frame bZIP CEBPA
    AML patients who benefit from transplantation in first remission?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - genetic#WT1
  - genetic#DNMT3A
  - genetic#FLT3-ITD
  - diagnosis#Bone-Marrow Multiparameter Flow MRD Assessment
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation
  rationale: >-
    One intensively treated cohort associated WT1, DNMT3A, immune/metabolic
    expression, and upfront transplant with outcome, whereas a larger pooled
    analysis found no independent overall-survival effect from several
    co-mutations. Flow MRD during consolidation is prognostic, but there is no
    validated CEBPA-specific randomized rule for transplant in first remission.
  evidence:
  - reference: PMID:38253683
    reference_title: Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent WT1 or DNMT3A mutations significantly predicted worse survival
      in AML patients with CEBPAbZIP-inf.
    explanation: This cohort supports one proposed adverse-risk signal.
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as
      ELN2022 adverse risk aberrations) had no independent impact on OS
    explanation: The pooled cohort provides a conflicting estimate, keeping a co-mutation-based transplant rule unresolved.
  proposed_experiments:
  - experiment_id: exp_cebpa_mrd_adapted_transplant_strategy
    name: Prospective MRD-adapted transplant strategy study
    description: >-
      Enroll molecularly defined in-frame bZIP CEBPA AML, stratify by harmonized
      co-mutation profile and consolidation-time bone-marrow flow MRD, and compare
      chemotherapy consolidation with allogeneic transplantation in the
      prespecified high-risk/MRD-positive strata.
    decision_criterion: >-
      A first-remission transplant rule would require a reproducible interaction
      showing improved overall survival, not only relapse reduction, with an
      acceptable non-relapse mortality tradeoff in an independent cohort.
- discussion_id: gap_cebpa_model_to_human_variant_fidelity
  prompt: >-
    Do p30-only and paired Cebpa knock-in mice reproduce the variant-specific
    human bZIP in-frame-indel outcome subgroup and its treatment response?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#N-Terminal CEBPA p42-to-p30 Dysregulation
  - pathophysiology#C-Terminal CEBPA bZIP DNA-Binding and Dimerization Dysfunction
  rationale: >-
    The mouse models establish etiologic and cellular effects of Cebpa isoform
    imbalance and paired terminal lesions, but human favorable risk is most
    clearly associated with diverse bZIP in-frame indels. The models do not
    reproduce the complete human allelic, co-mutation, immune/metabolic, and
    treatment-context landscape.
  evidence:
  - reference: PMID:18394553
    reference_title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To mimic the most common mutations affecting CEBPA-that is, those leading
      to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa
      isoform (p30)-we modified the mouse Cebpa locus to express only p30.
    explanation: The model deliberately isolates the N-terminal isoform consequence rather than the full human genotype spectrum.
  - reference: PMID:19878871
    reference_title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We here use knockin mutagenesis in the mouse to model the spectrum of
      acquired CEBPA mutations in human acute myeloid leukemia.
    explanation: The paired knock-in system provides mechanistic precedent but still abstracts heterogeneous human alleles.
  proposed_experiments:
  - experiment_id: exp_cebpa_isogenic_human_variant_panel
    name: Isogenic human CEBPA variant-panel leukemia model
    description: >-
      Engineer representative N-terminal truncating, bZIP in-frame indel, bZIP
      stop, and bZIP missense alleles singly and in phased pairs in human CD34+
      hematopoietic cells, with matched xenografts and drug-response profiling.
    decision_criterion: >-
      Model fidelity would be supported if variant classes reproduce the human
      hierarchy of differentiation arrest, stem/progenitor state, transcriptome,
      chemotherapy sensitivity, and relapse-associated MRD in independent donors.
datasets: []
references:
- reference: PMID:35732831
  title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
- reference: DOI:10.1007/s11899-023-00699-3
  title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
- reference: PMID:34320176
  title: "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome."
- reference: PMID:38228680
  title: Prognostic impact of CEBPA mutational subgroups in adult AML.
- reference: PMID:11242107
  title: "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia."
- reference: PMID:18394553
  title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
- reference: PMID:19878871
  title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
notes: >-
  Comprehensive somatic-scope re-review. The entry deliberately separates
  WHO-HAEM5 and ICC disease definitions from ELN treatment-context risk, limits
  favorable prognosis to the supported in-frame bZIP subgroup, and treats
  germline CEBPA predisposition as a differential requiring constitutional
  testing. Co-mutation effects, immune/metabolic signatures, first-remission
  transplant selection, and CEBPA-focused trials remain qualified rather than
  encoded as settled efficacy claims. No approved CEBPA-directed drug exists.
📚

References & Deep Research

References

7
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.
DOI:10.1007/s11899-023-00699-3
Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations
No top-level findings curated for this source.
PMID:34320176
CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.
No top-level findings curated for this source.
PMID:38228680
Prognostic impact of CEBPA mutational subgroups in adult AML.
No top-level findings curated for this source.
PMID:11242107
Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.
No top-level findings curated for this source.
PMID:18394553
Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
No top-level findings curated for this source.
PMID:19878871
Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 59 citations 2026-05-11T09:23:07.543451

1. Disease Information

1.1 Concise overview

AML is a clonal hematopoietic malignancy characterized by expansion of immature myeloid blasts in bone marrow and blood, resulting in marrow failure and ineffective hematopoiesis (cytopenias and related complications). (debnath2024prognosisandtreatment pages 1-2)

A clinically important genetically defined subset is AML with somatic mutation(s) in the transcription factor CEBPA (CCAAT/enhancer-binding protein alpha), whose altered function disrupts myeloid differentiation and is associated with characteristic prognostic and classification features, especially when mutations are in-frame insertions/deletions in the basic leucine zipper (bZIP) domain. (sargas2023comparisonofthe pages 1-2, mrozek2023outcomepredictionby pages 1-2)

1.2 Synonyms and alternative names used in recent authoritative sources

Recent classification/guideline literature uses multiple labels for overlapping but non-identical sets of cases: - “AML with CEBPA mutation” (WHO 2022 label in comparative reviews). (park2024whatisnew pages 1-2, park2024whatisnew pages 2-3) - “AML with mutated bZIP CEBPA” (ICC 2022 label). (park2024whatisnew pages 1-2) - biCEBPA (biallelic), smbZIP-CEBPA (single bZIP mutation) in WHO/ICC comparisons. (salman2024comparativeanalysisof pages 2-4, park2024whatisnew pages 1-2) - CEBPAdm (double-mutant/biallelic), CEBPAsm (single-mutant/monoallelic), CEBPAbZIP-inf (bZIP in-frame) in clinical/prognostic studies. (tien2024dysregulatedimmuneand pages 1-2, yuan2023sporadicandfamilial pages 5-6)

1.3 Classification context (WHO 2022 vs ICC 2022 vs ELN 2022)

  • WHO 2022: includes both biallelic CEBPA and single bZIP-region mutations (smbZIP-CEBPA) under “AML with CEBPA mutation” in comparative descriptions; a ≥20% blast threshold is described for AML with CEBPA mutation in a classification comparison review. (park2024whatisnew pages 1-2, park2024whatisnew pages 2-3)
  • ICC 2022: emphasizes in-frame bZIP CEBPA mutations and applies a ≥10% blast cutoff for AML with recurrent genetic abnormalities (including CEBPA-defined AML). (salman2024comparativeanalysisof pages 2-4, park2024whatisnew pages 1-2)
  • ELN 2022 (risk stratification): revised favorable-risk criterion from biallelic CEBPA (ELN 2017) to in-frame bZIP CEBPA mutations, regardless of monoallelic vs biallelic state. (sargas2023comparisonofthe pages 1-2, mrozek2023outcomepredictionby pages 1-2)

Visual evidence summarizing WHO vs ICC differences is available in a WHO/ICC comparison figure. (salman2024comparativeanalysisof media e167dd0e)

2. Etiology

2.1 Primary causal factors

  • Somatic driver mutations in CEBPA: AML in this entity is primarily driven/defined by acquired mutations affecting CEBPA—often involving N-terminal transactivation domain (TAD) and/or C-terminal bZIP domain, with specific mutation classes carrying distinct prognostic implications. (georgi2024prognosticimpactof pages 1-2, faisal2023locationlocationlocation pages 1-3)

2.2 Risk factors

Genetic risk factors (germline predisposition vs somatic)

  • A minority of patients with CEBPA-mutated AML carry germline CEBPA variants; one review estimates ~10% of CEBPA-mutated AML may have germline CEBPA. (yuan2023sporadicandfamilial pages 4-5)
  • For germline predisposition, N-terminal germline variants have been described with high penetrance and earlier onset; familial cases often acquire a second somatic C-terminal mutation. (yuan2023sporadicandfamilial pages 4-5, tawana2017familialcebpamutatedacute pages 1-4)

Environmental/occupational and therapy-related factors for AML broadly

Recent reviews summarize established AML risk contexts: - Ionizing radiation exposure and chemical exposures including benzene and other solvents are explicitly described as AML risk factors, along with tobacco use; therapy-related AML after prior radiation/cytotoxic agents is also described. (marrero2023currentlandscapeof pages 1-2) - A systematic review/meta-analysis notes radiation increases leukemia risk and that aromatic compounds (benzene, toluene, xylene) have a strong association with AML; it also notes significantly elevated risk of therapy-related AML following chemotherapy. (shen2023associationbetweenmetal(loid)s pages 1-2) - A mechanistic review details benzene metabolism (notably via CYP2E1) producing reactive metabolites that contribute to hematopoietic/bone-marrow injury relevant to leukemogenesis. (sandoval2023anupdatedoverview pages 7-9)

2.3 Protective factors

No specific protective genetic variants or modifiable protective exposures were identified in the retrieved full texts for this entity.

2.4 Gene–environment interactions

Evidence in AML broadly (not specific to CEBPA-mutated AML) indicates that polymorphisms in xenobiotic-metabolism genes can modify leukemia/cancer risk; examples reported include CYP2E1, GSTM1, NQO1, NAT2, MDR1 and broader CYP450 SNPs. (sandoval2023anupdatedoverview pages 7-9)

3. Phenotypes

3.1 Core clinical presentation (AML overall)

AML frequently presents with bone marrow failure manifestations and may also show extramedullary involvement. - Cytopenia-related symptoms and complications include anemia, bleeding, and infections. (rivera2023mutationsinthe pages 2-2, leoni2025…genemutationsby pages 11-15) - Organ infiltration can involve spleen, liver, skin, gums, and sometimes CNS. (rivera2023mutationsinthe pages 2-2, leoni2025…genemutationsby pages 11-15)

3.2 CEBPA-mutated AML clinical correlates

  • Morphologic subtypes commonly reported include FAB M1, M2, or M4; karyotype is often normal or intermediate-risk. (yuan2023sporadicandfamilial pages 4-5)
  • Familial CEBPA AML may present without preceding abnormal blood counts or myelodysplasia. (yuan2023sporadicandfamilial pages 4-5, tawana2017familialcebpamutatedacute pages 1-4)

3.3 Suggested HPO terms (examples)

(Representative mapping for knowledge-base use; frequency data are limited in retrieved texts.) - Cytopenias / marrow failure: Anemia (HP:0001903), Thrombocytopenia (HP:0001873), Neutropenia (HP:0001875), Pancytopenia (HP:0001876). (leoni2025…genemutationsby pages 11-15, debnath2024prognosisandtreatment pages 1-2) - Bleeding manifestations: Epistaxis (HP:0000421), Purpura (HP:0000979), Gingival bleeding (HP:0000225). (leoni2025…genemutationsby pages 11-15) - Infection susceptibility: Recurrent infections (HP:0002719), Fever (HP:0001945). (leoni2025…genemutationsby pages 11-15) - Extramedullary disease: Hepatomegaly (HP:0002240), Splenomegaly (HP:0001744), Cutaneous infiltration (suggest: Skin infiltration, HP:0001031 as a broad proxy), Central nervous system involvement (HP:0001298 for encephalopathy as proxy; CNS leukemia lacks a perfect single HPO term in this corpus). (rivera2023mutationsinthe pages 2-2, leoni2025…genemutationsby pages 11-15)

4. Genetic / Molecular Information

4.1 Causal gene

  • CEBPA (CCAAT/enhancer-binding protein alpha), a myeloid transcription factor; produces p42 and p30 isoforms. (brown2020secondaryleukemiain pages 10-11)

4.2 Pathogenic somatic variant classes (current understanding)

Authoritative 2023–2024 sources emphasize that where and what type of CEBPA mutation occurs matters for classification and prognosis: - bZIP in-frame insertions/deletions (bZIPInDel / CEBPAbZIP-inf): central favorable-risk driver class in ELN 2022. (sargas2023comparisonofthe pages 1-2, mrozek2023outcomepredictionby pages 1-2) - Other bZIP lesions: missense substitutions (bZIPms) and truncating/stop-inducing lesions (bZIPSTOP) are less favorable as a group than bZIPInDel in pooled analyses. (georgi2024prognosticimpactof pages 1-2, georgi2024prognosticimpactof pages 2-3) - N-terminal TAD mutations and combinations with bZIP changes define classic “double-mutant” patterns; prognostic implications are heterogeneous and refined by domain/type. (georgi2024prognosticimpactof pages 1-2, rivera2023mutationsinthe pages 3-4)

4.3 Allelic state (monoallelic vs biallelic)

CEBPAdm (double-mutant/biallelic) and CEBPAsm (single-mutant) are widely used categories, but recent analyses suggest that bZIP in-frame genotype is more prognostically determinant than “biallelic” status alone. (georgi2024prognosticimpactof pages 1-2, sargas2023comparisonofthe pages 1-2)

4.4 Co-mutation patterns

  • In one 2023 review synthesis, CEBPAdm commonly co-mutates with GATA2, WT1, ASXL1, TET2, NRAS, whereas CEBPAsm more often co-mutates with FLT3, NPM1, IDH1/2, RUNX1 (also ASXL1, TET2). (yuan2023sporadicandfamilial pages 4-5)
  • In an ELN-favorable bZIP-inframe cohort, WT1 or DNMT3A co-mutation was associated with worse survival. (tien2024dysregulatedimmuneand pages 1-2)

4.5 Molecular profiling signals (recent 2024 work)

A 2024 transcriptomic study of CEBPAbZIP-inf AML linked poor outcomes to: - Enrichment of interferon (IFN) signaling and metabolic/mitochondrial pathways (e.g., mitochondrial complex genes) in patients with shorter event-free survival. (tien2024dysregulatedimmuneand pages 1-2)

5. Mechanism / Pathophysiology

5.1 Causal chain (from mutation to phenotype)

A convergent mechanistic model supported by human and model-organism data: 1. CEBPA alteration (domain-specific mutation or isoform imbalance) perturbs transcriptional programs essential for granulocytic differentiation and normal myeloid maturation. (tawana2017familialcebpamutatedacute pages 1-4, brown2020secondaryleukemiain pages 10-11) 2. Disruption impairs the transition from common myeloid progenitor (CMP) to granulocyte–macrophage progenitor (GMP), contributing to differentiation block and accumulation of blasts. (tawana2017familialcebpamutatedacute pages 1-4) 3. In some experimental settings, CEBPA alterations promote HSPC expansion/self-renewal, creating a substrate for leukemogenesis and clinical AML. (chen2024cebpaisrequired pages 1-2, chen2024cebpaisrequired pages 11-11)

5.2 Downstream targets and pathways

  • CEBPA p42 drives myeloid differentiation by inducing targets including SPI1, CSF3R, IL6R, GFI1B, KLF1, KLF5; p30 can inhibit p42 activity. (brown2020secondaryleukemiain pages 10-11)
  • In CEBPAbZIP-inf AML, poor-outcome signatures include IFN signaling and mitochondrial metabolic programs. (tien2024dysregulatedimmuneand pages 1-2)

5.3 Suggested ontology terms

  • GO Biological Process (examples): granulocyte differentiation; myeloid cell differentiation; regulation of transcription by RNA polymerase II; hematopoietic stem cell proliferation; interferon signaling pathway; oxidative phosphorylation/mitochondrial electron transport (as pathway proxies for the transcriptomic signals). (tien2024dysregulatedimmuneand pages 1-2, tawana2017familialcebpamutatedacute pages 1-4, brown2020secondaryleukemiain pages 10-11, chen2024cebpaisrequired pages 1-2)
  • CL cell types (examples): hematopoietic stem cell; common myeloid progenitor; granulocyte–macrophage progenitor; myeloblast. (tawana2017familialcebpamutatedacute pages 1-4, chen2024cebpaisrequired pages 1-2)

6. Anatomical Structures Affected

  • Primary site: Bone marrow (hematopoietic tissue) with spillover of blasts into peripheral blood. (debnath2024prognosisandtreatment pages 1-2)
  • Secondary/extramedullary sites: spleen, liver, skin, gums, CNS may be infiltrated. (rivera2023mutationsinthe pages 2-2, leoni2025…genemutationsby pages 11-15)

Suggested anatomy terms: - UBERON: bone marrow; peripheral blood; spleen; liver; skin; central nervous system. (rivera2023mutationsinthe pages 2-2, leoni2025…genemutationsby pages 11-15, debnath2024prognosisandtreatment pages 1-2)

7. Temporal Development

  • AML is generally acute/subacute in presentation, often with symptoms over weeks to months and complications of marrow failure. (leoni2025…genemutationsby pages 11-15)
  • For familial/germline CEBPA predisposition (important differential when “somatic CEBPA AML” is suspected), N-terminal germline variants were reported with high penetrance and median onset ~25 years (range ~1.75–46), with most frequent presentation ages 21–30. (yuan2023sporadicandfamilial pages 4-5)

8. Inheritance and Population

8.1 Epidemiology

  • General AML incidence reported as ~3–5 per 100,000 with average age ~65 years. (rivera2023mutationsinthe pages 2-2)
  • CEBPA mutations are reported in ~5–14% of AML. (rivera2023mutationsinthe pages 2-2)
  • In a uniformly treated adult cohort, 142/887 (16%) had CEBPA mutations and 113/887 (12.7%) had CEBPAbZIP-inf. (tien2024dysregulatedimmuneand pages 1-2)

8.2 Germline predisposition (distinct but clinically relevant)

  • Familial CEBPA AML is autosomal dominant; onset can range from childhood to adulthood; familial cases may relapse as independent episodes and have high recurrence. (tawana2017familialcebpamutatedacute pages 1-4)
  • Germline CEBPA predisposition frequency was reported as rare in AML (on the order of <1% in one review of germline TF predisposition). (brown2020secondaryleukemiain pages 10-11)

9. Diagnostics

9.1 Recommended molecular testing strategy for CEBPA

  • Full-length sequencing of CEBPA (single exon) is recommended as the most comprehensive approach; targeted NGS panels are favored over Sanger due to higher sensitivity (~5% vs ~15–20%). (yuan2023sporadicandfamilial pages 4-5)
  • Capture-based NGS is preferred over amplicon-based approaches for CEBPA because indels are common and the locus is GC-rich; fragment analysis can screen indels (analytic sensitivity ~5%) but cannot detect point mutations or precisely define indels. (yuan2023sporadicandfamilial pages 5-6)

9.2 Determining allelic state and excluding germline

  • Routine short-read sequencing may not reliably determine cis/trans configuration for distant N- and C-terminal mutations. (yuan2023sporadicandfamilial pages 5-6)
  • Germline testing requires non-hematopoietic tissue (cultured skin fibroblasts preferred in the reviewed guidance); persistence of a CEBPA variant at complete remission should trigger germline evaluation. (yuan2023sporadicandfamilial pages 5-6, yuan2023sporadicandfamilial pages 4-5)

9.3 MRD assessment

  • Multiparameter flow cytometry (MFC) MRD is in clinical use; MRD positivity during consolidation predicted higher relapse and worse relapse-free survival in CEBPA-mutated AML in a review synthesis. (yuan2023sporadicandfamilial pages 5-6)

10. Outcome / Prognosis

10.1 Key prognostic concept (2023–2024 update)

A major 2022–2024 refinement is that favorable outcomes are best associated with in-frame bZIP mutations rather than “biallelic CEBPA” broadly. (sargas2023comparisonofthe pages 1-2, mrozek2023outcomepredictionby pages 1-2)

10.2 Recent statistics (prioritizing 2023–2024)

  • PETHEMA registry (2024, intensively treated): CEBPA-bZIP-inframe patients had estimated 3-year OS 83.3% (95% CI 58.3–100). (torre2024validationofmutated pages 1-2)
  • CEBPAbZIP-inf heterogeneity (2024): in a cohort study, despite ELN-2022 favorable classification, 5-year EFS was <50% and cumulative relapse ~40%, with worse survival in those co-mutated for WT1 or DNMT3A. (tien2024dysregulatedimmuneand pages 1-2)
  • Normal karyotype AML multivariable (2023): bZIP in-frame CEBPA mutation was independently favorable (e.g., OS HR 0.49). (ahn2023clinicalsignificanceof pages 4-5)

10.3 Abstract-supported statements (direct quotes)

  • ELN 2022 favorable-risk framing: “Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients.” (tien2024dysregulatedimmuneand pages 1-2)
  • Molecular findings linked to poor outcome: “Concurrent WT1 or DNMT3A mutations significantly predicted worse survival…” (tien2024dysregulatedimmuneand pages 1-2)

11. Treatment

11.1 Standard of care (real-world implementation)

  • A recent review notes AML-CEBPA is chemosensitive and commonly treated with anthracycline + cytarabine induction and consolidation. (yuan2023sporadicandfamilial pages 5-6)

11.2 Allogeneic HSCT considerations

  • For germline/familial CEBPA AML, relapse can be frequent and may represent independent episodes; allogeneic HSCT is considered in recurrent/high-risk settings (also to avoid transplanting from a related donor who may carry the germline variant). (tawana2017familialcebpamutatedacute pages 1-4)
  • In bZIP-inframe AML with poor-outcome biology (e.g., adverse co-mutations or transcriptomic risk states), authors have suggested that upfront allo-transplant may improve long-term control. (tien2024dysregulatedimmuneand pages 1-2)

11.3 Clinical trials (examples from ClinicalTrials.gov)

  • NCT06458257: observational study evaluating allogeneic HSCT in “high-relapse-risk CEBPA mutant AML.” (rivera2023mutationsinthe pages 3-4)
  • NCT06529250 / NCT04415008: HAD-based intensified cytarabine regimens for CEBPA double-mutated AML. (rivera2023mutationsinthe pages 3-4)
  • NCT07451912: venetoclax + hypomethylating agents + subcutaneous cytarabine for CEBPA-mutated AML. (rivera2023mutationsinthe pages 3-4)

11.4 Suggested MAXO terms (examples)

  • Induction chemotherapy; Consolidation chemotherapy; Allogeneic hematopoietic stem cell transplantation; Measurable residual disease monitoring; Targeted therapy with BCL2 inhibitor (venetoclax-based regimen). (tien2024dysregulatedimmuneand pages 1-2, rivera2023mutationsinthe pages 3-4, yuan2023sporadicandfamilial pages 5-6)

12. Prevention

  • Primary prevention (AML overall): reduction of exposure to established leukemogens (e.g., benzene) and avoiding unnecessary ionizing radiation where feasible; these are supported as risk factors in AML review literature, but specific prevention trials for this entity were not found in the retrieved corpus. (shen2023associationbetweenmetal(loid)s pages 1-2, marrero2023currentlandscapeof pages 1-2)
  • Secondary prevention: no population screening specific to CEBPA somatic AML; however, in suspected hereditary contexts (familial AML), genetic counseling and constitutional testing can guide surveillance and donor selection. (yuan2023sporadicandfamilial pages 5-6, tawana2017familialcebpamutatedacute pages 1-4)

13. Other Species / Natural Disease

No naturally occurring non-human “CEBPA-mutated AML” entity was identified in the retrieved texts; mechanistic insights rely primarily on engineered or experimentally induced models (see Model Organisms).

14. Model Organisms

14.1 Zebrafish

  • Zebrafish cebpa mutants were used to define roles of Cebpa in HSPC generation and myeloid differentiation; complete loss reduced early HSPC generation and increased apoptosis; epistasis placed Cebpa downstream of Runx1. (chen2024cebpaisrequired pages 1-2, chen2024cebpaisrequired pages 6-7)

14.2 Mouse

  • CEBPA knockout mice demonstrate granulopoiesis defects (“lack mature granulocytes”), supporting CEBPA’s essential role in granulocyte development. (faisal2023locationlocationlocation pages 1-3)
  • A knock-in model with C-terminal/bZIP in-frame mutation (CEBPAK313KK) has been described as promoting intrinsic HSPC expansion and accelerating AML progression in a mutant background. (chen2024cebpaisrequired pages 11-11)

Evidence Map (2022–2024 classification/prognosis/diagnostics)

The following table consolidates high-yield evidence items (classification criteria, prognosis statistics, diagnostics/MRD notes, and example clinical trials) for rapid knowledge-base extraction.

Topic Key points Study/source (author year journal) PMID URL Evidence context ID(s)
WHO 2022 classification WHO 2022 entity is “AML with CEBPA mutation”; includes both biallelic CEBPA and single mutations in the basic leucine zipper (bZIP) region; blast threshold described as ≥20% for this context in comparative reviews. Park 2024 Blood Research https://doi.org/10.1007/s44313-024-00016-8 (park2024whatisnew pages 1-2, park2024whatisnew pages 2-3)
ICC 2022 classification ICC 2022 entity is “AML with mutated bZIP CEBPA”; focuses on in-frame bZIP CEBPA mutations and uses a ≥10% blast threshold for recurrent genetic abnormality-defined AML. Salman 2024 Cancers; Park 2024 Blood Research https://doi.org/10.3390/cancers16162915 ; https://doi.org/10.1007/s44313-024-00016-8 (salman2024comparativeanalysisof pages 2-4, park2024whatisnew pages 1-2, salman2024comparativeanalysisof pages 4-6)
ELN 2022 risk definition ELN 2022 favorable-risk category replaced “biallelic CEBPA” with in-frame bZIP CEBPA mutations, irrespective of monoallelic vs biallelic status. Sargas 2023 Blood Cancer Journal; Huber 2023 Leukemia; Mrózek 2023 Leukemia https://doi.org/10.1038/s41408-023-00835-5 ; https://doi.org/10.1038/s41375-023-01909-w ; https://doi.org/10.1038/s41375-023-01846-8 (sargas2023comparisonofthe pages 1-2, huber2023amlclassificationin pages 1-2, mrozek2023outcomepredictionby pages 1-2)
Prognostic subgroup refinement In pooled analysis of 1,010 adult CEBPA-mutant AML cases, only bZIP in-frame insertion/deletion (bZIPInDel) cases had significantly higher CR rates and longer relapse-free and overall survival than other CEBPA-mutant subgroups; bZIPSTOP, bZIP missense, and TAD-mutant groups were less favorable. Georgi 2024 Leukemia https://doi.org/10.1038/s41375-024-02140-x (georgi2024prognosticimpactof pages 1-2, georgi2024prognosticimpactof pages 2-3)
Prognosis in CEBPAbZIP-inf with co-mutations In 887 non-M3 AML patients, 142/887 (16%) had CEBPA mutations and 113/887 (12.7%) had CEBPAbZIP-inf; 96/113 (85.0%) biallelic. Despite favorable ELN assignment, 5-year EFS was reported as <50% and cumulative relapse near 40%; concurrent WT1 or DNMT3A predicted worse survival. Tien 2024 Blood Cancer Journal https://doi.org/10.1038/s41408-023-00975-8 (tien2024dysregulatedimmuneand pages 1-2)
PETHEMA registry outcomes In 696 intensively treated AML patients, 82 (11.8%) had CEBPA mutations; 45 had bZIP mutations and 40 had CEBPA-bZIP-inf (5.7%). Estimated 3-year OS was 83.3% (95% CI 58.3–100) for CEBPA-bZIP-inf vs 54.3% for other CEBPA mutations and 47.2% for CEBPA wild type; historical relapse risk cited ~40% for CEBPAdm vs ~60% for CEBPAsm. De la Torre 2024 Haematologica https://doi.org/10.3324/haematol.2023.284601 (torre2024validationofmutated pages 1-2)
Normal-karyotype AML multivariable outcomes In normal-karyotype AML, bZIP in-frame CEBPA mutation was an independent favorable factor: CR OR 3.97 (95% CI 1.16–13.50, p=0.028), OS HR 0.49 (0.30–0.81, p=0.006), RFS HR 0.56 (0.35–0.91, p=0.019), CIR HR 0.49 (0.25–0.96, p=0.036). FLT3-ITD remained adverse. Ahn 2023 Cancer Research and Treatment https://doi.org/10.4143/crt.2022.1407 (ahn2023clinicalsignificanceof pages 4-5)
Mini-review summary of older cohorts Review summarized favorable outcomes for biallelic and monoallelic in-frame bZIP groups: median OS 103.2 months for CEBPAbi vs 21.9 months for CEBPAmono vs 19.3 months for CEBPAwt; pediatric series showed CR 87.7% vs 76.9% and MRD-negative CR 83.4% vs 70.5% for CEBPAm vs CEBPAwt; 5-year EFS/OS around 64%/81–89% for CEBPAbi and CEBPAsmbZIP in cited cohorts. Faisal 2023 Leukemia Research Reports https://doi.org/10.1016/j.lrr.2023.100386 (faisal2023locationlocationlocation pages 1-3)
Diagnostic testing: sequencing strategy Full-length sequencing of the single-exon CEBPA gene is recommended; routine NGS panels are favored over Sanger because of higher sensitivity (~5% for NGS vs ~15–20% for Sanger). Capture-based NGS is preferred over amplicon-based approaches for CEBPA because indels are common and GC-rich sequence complicates testing. Yuan 2023 Current Hematologic Malignancy Reports https://doi.org/10.1007/s11899-023-00699-3 (yuan2023sporadicandfamilial pages 5-6, yuan2023sporadicandfamilial pages 4-5)
Diagnostic testing: fragment analysis Fragment analysis can be used pragmatically to screen for indels in resource-limited settings with analytic sensitivity around 5%, but it cannot detect point mutations or precisely define indel sequence/size. Yuan 2023 Current Hematologic Malignancy Reports https://doi.org/10.1007/s11899-023-00699-3 (yuan2023sporadicandfamilial pages 5-6)
Diagnostic testing: allelic status/germline caveat Standard Sanger or short-read routine NGS cannot reliably establish cis/trans configuration for distant N- and C-terminal mutations; constitutional non-hematopoietic tissue (cultured skin fibroblasts preferred) is required to confirm germline status. Persistence of CEBPA mutation in remission should prompt germline evaluation. Yuan 2023 Current Hematologic Malignancy Reports https://doi.org/10.1007/s11899-023-00699-3 (yuan2023sporadicandfamilial pages 5-6, yuan2023sporadicandfamilial pages 4-5)
MRD notes Multiparametric flow cytometry (MFC) MRD is in clinical use; MRD positivity during consolidation (rather than necessarily after induction) predicts higher relapse and worse RFS. “Low-risk MRD” was defined as negative MRD after at least two consolidation cycles and associated with better RFS/OS. Yuan 2023 Current Hematologic Malignancy Reports https://doi.org/10.1007/s11899-023-00699-3 (yuan2023sporadicandfamilial pages 5-6)
Clinical trial example NCT06458257: “The Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Newly Diagnosed High-relapse-risk CEBPA Mutant Acute Myeloid Leukemia”; recruiting observational study; target enrollment 50. ClinicalTrials.gov record https://clinicaltrials.gov/study/NCT06458257 (rivera2023mutationsinthe pages 3-4)
Clinical trial example NCT06529250: “Intermediate-dose HAD Regimen for CEBPA Double-mutated AML”; recruiting interventional study; phase NA; enrollment 148. ClinicalTrials.gov record https://clinicaltrials.gov/study/NCT06529250 (rivera2023mutationsinthe pages 3-4)
Clinical trial example NCT04415008: “Efficacy of HAD Induction With Intensified Cytarabine in Newly-diagnosed CEBPA Double Mutated Acute Myeloid Leukemia”; active, not recruiting; phase 2; enrollment 61. ClinicalTrials.gov record https://clinicaltrials.gov/study/NCT04415008 (rivera2023mutationsinthe pages 3-4)
Clinical trial example NCT07451912: “Venetoclax Plus Hypomethylating Agents and Subcutaneous Cytarabine for CEBPA-Mutated AML”; recruiting interventional study; phase 1/2; enrollment 29. ClinicalTrials.gov record https://clinicaltrials.gov/study/NCT07451912 (rivera2023mutationsinthe pages 3-4)

Table: This table consolidates classification criteria, prognosis, diagnostics/MRD, and example clinical trials for AML with CEBPA mutations. It is useful as a compact evidence map for populating a disease knowledge base entry with recent, citable findings.

Key limitations of this evidence snapshot

  1. Ontology identifiers (MONDO/MeSH/ICD/Orphanet/OMIM) for the specific “AML with CEBPA somatic mutations” entity were not present in the retrieved full texts and therefore could not be cited here.
  2. Many phenotype frequencies for the somatic (non-familial) CEBPA-mutated AML subgroup are not consistently reported in the retrieved 2023–2024 sources; most symptom frequencies derive from AML-wide literature.
  3. Variant-level population allele frequencies (gnomAD) and clinical variant assertions (ClinVar/COSMIC IDs) were not retrieved in this run.

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