Acute Myeloid Leukemia with CEBPA Somatic Mutations

MONDO:0017894 Pathograph 5 acute myeloid leukemia

Acute myeloid leukemia with CEBPA somatic mutations is a molecularly defined AML subtype driven by acquired CEBPA alterations, especially bZIP in-frame mutations that define a favorable-risk genetic entity in current AML classifications. CEBPA encodes a myeloid transcription factor required for granulocytic differentiation; pathogenic disruption produces impaired myeloid maturation, blast accumulation in blood and marrow, and cytopenia-related complications. Outcomes are heterogeneous and are modified by mutation location, allelic state, and co-mutations such as WT1, DNMT3A, FLT3-ITD, and chromatin/cohesin/splicing gene lesions.

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0
Mappings
0
Definitions
0
Inheritance
7
Pathophysiology
1
Histopathology
11
Phenotypes
5
Pathograph
5
Genes
3
Treatments
2
Subtypes
0
Differentials
0
Datasets
3
Trials
0
Models
1
Deep Research
🏷

Classifications

Harrison's Chapter
cancer hematologic malignancy
ICD-O Morphology
Leukemia
◆

Subtypes

2
AML with CEBPA bZIP in-frame mutation
Approximately 5-6% of intensively treated AML in recent cohorts
AML with in-frame mutations in the C-terminal basic leucine zipper region of CEBPA. This subgroup corresponds to the most consistently favorable-risk CEBPA-mutated AML group, though adverse co-mutation patterns and immune or metabolic transcriptional programs can identify higher-relapse-risk cases.
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."
This pooled adult AML cohort supports bZIP in-frame/insertion-deletion mutations as the favorable CEBPA-mutated subgroup.
Other CEBPA-Mutated AML
CEBPA-mutated AML without the favorable bZIP in-frame pattern, including non-bZIP, bZIP stop, bZIP missense, or TAD-only mutation patterns. These cases may not share the same favorable prognosis and require risk stratification using the broader AML molecular context.
Show evidence (1 reference)
PMID:37680323 SUPPORT Other
"Whereas prior iterations did not specify the type of CEBPA mutation, the updated schema specify that only mutations localized to the C-terminal basic zipper (bZIP) domain are considered prognostically favorable."
This review explains why mutation location distinguishes favorable bZIP disease from other CEBPA-mutated AML patterns.
⚙

Pathophysiology

7
CEBPA Transcription Factor Disruption
Somatic CEBPA mutations disrupt the activity of CCAAT/enhancer-binding protein alpha, a transcription factor that maintains the balance between myeloid progenitor proliferation and differentiation. Pathogenic disruption weakens the normal transcriptional program needed for granulocytic maturation.
hematopoietic multipotent progenitor cell link
myeloid cell differentiation link ↓ DECREASED
DNA-binding transcription factor activity link ↓ DECREASED
Downstream
Myeloid Differentiation Block Impaired CEBPA activity prevents normal granulocytic maturation.
Show evidence (1 reference)
PMID:37621152 SUPPORT Human Clinical
"Among them, the CCAAT-enhancer-binding protein alpha (CEBPA) plays a crucial role in maintaining the balance between myeloid proliferation and differentiation."
This supports CEBPA as the transcription factor whose disruption alters the proliferation-differentiation balance in myeloid cells.
Myeloid Differentiation Block
Impaired CEBPA-mediated transcription favors arrested myeloid maturation. Immature blasts persist in an undifferentiated state and begin to accumulate in marrow and peripheral blood.
myeloblast link
negative regulation of cell differentiation link ↑ INCREASED
bone marrow link
Downstream
Bone Marrow and Blood Blast Accumulation Arrested myeloblasts expand and replace normal hematopoiesis.
Show evidence (1 reference)
PMID:37621152 SUPPORT Human Clinical
"Imbalances in this network can lead to disrupted differentiation and contribute to the development of malignant diseases."
The abstract links CEBPA transcription-factor network imbalance to disrupted differentiation in malignant hematologic disease.
Bone Marrow and Blood Blast Accumulation
Leukemic myeloblasts accumulate in bone marrow and may circulate in blood, meeting the morphologic framework of AML and suppressing normal erythroid, granulocytic, and megakaryocytic output.
myeloblast link
cell population proliferation link ↑ INCREASED
bone marrow link blood link
Downstream
Bone Marrow Failure Blast expansion suppresses normal hematopoiesis and causes cytopenias.
Show evidence (1 reference)
PMID:23590662 SUPPORT Other
"Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by ≥20% myeloblasts in the blood or bone marrow."
This AML diagnostic review supports the core blast-accumulation feature in blood or bone marrow.
Bone Marrow Failure
Marrow replacement by leukemic blasts produces anemia, thrombocytopenia, and neutropenia, causing fatigue, bleeding, and infection susceptibility.
bone marrow link
Downstream
Cytopenia-Associated Complications Reduced mature blood-cell production causes AML presentation symptoms.
Show evidence (1 reference)
PMID:37769139 SUPPORT Human Clinical
"Bone marrow aspirate showed infiltration by 45% of myeloblasts and myelodysplasia."
This AML case report supports marrow infiltration by myeloblasts as the substrate for marrow-failure presentation.
Cytopenia-Associated Complications
Cytopenias from marrow failure cause the major presenting complications of AML, including pancytopenia, fatigue from anemia, bleeding from thrombocytopenia, and infection risk from neutropenia.
blood link
Show evidence (1 reference)
PMID:37769139 SUPPORT Human Clinical
"AML that is presented as pancytopenia should be considered in the evaluation of marrow failure syndrome."
This case-report abstract directly links AML pancytopenia presentation to marrow failure evaluation.
IFN and Metabolic Transcriptomic Risk Program
Within CEBPA bZIP in-frame AML, some patients show immune and metabolic transcriptional programs associated with shorter event-free survival, including interferon-stimulated gene expression and mitochondrial complex gene overexpression.
immune response link ↑ INCREASED regulation of transcription by RNA polymerase II link ⚠ ABNORMAL
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 immune and metabolic pathway activation as a prognostic transcriptomic program in this subtype.
CEBPA-Dependent Hematopoietic Progenitor Maintenance
Model-organism evidence supports a conserved role for Cebpa in hematopoietic stem and progenitor cell generation, maintenance, and myeloid differentiation, providing mechanistic context for how CEBPA dysfunction can disturb blood-cell development.
hematopoietic stem cell link
myeloid cell differentiation link ↓ DECREASED
Show evidence (1 reference)
PMID:39500381 SUPPORT Model Organism
"The CCAAT enhancer binding protein alpha (CEBPA) is crucial for myeloid differentiation and the balance of haematopoietic stem and progenitor cell (HSPC) quiescence and self-renewal, and its dysfunction can drive leukemogenesis."
This zebrafish study supports the conserved developmental role of Cebpa in hematopoietic progenitors and leukemogenesis.
✶

Histopathology

1
Myeloblast Predominance VERY_FREQUENT
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.
●

Phenotypes

11
Blood 7
Leukemia Leukemia (HP:0001909)
Show evidence (1 reference)
PMID:23590662 SUPPORT Other
"Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by ≥20% myeloblasts in the blood or bone marrow."
This supports the leukemia phenotype as a myeloid neoplasm with blood or marrow myeloblast accumulation.
Pancytopenia Pancytopenia (HP:0001876)
Anemia Anemia (HP:0001903)
Thrombocytopenia Thrombocytopenia (HP:0001873)
Neutropenia Decreased total neutrophil count (HP:0001875)
Leukocytosis Increased total leukocyte count (HP:0001974)
Abnormal Bleeding Abnormal bleeding (HP:0001892)
Cardiovascular 1
Splenomegaly Splenomegaly (HP:0001744)
Digestive 1
Hepatomegaly Hepatomegaly (HP:0002240)
Immune 1
Recurrent Infections Recurrent infections (HP:0002719)
Constitutional 1
Fatigue Fatigue (HP:0012378)
🧬

Genetic Associations

5
CEBPA (Somatic driver mutation defining AML-CEBPA)
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.
WT1 (Adverse co-mutation in CEBPA bZIP in-frame AML)
Show evidence (1 reference)
PMID:38253683 SUPPORT Human Clinical
"Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf."
This supports WT1 and DNMT3A co-mutations as adverse modifiers in CEBPA bZIP in-frame AML.
DNMT3A (Adverse co-mutation in CEBPA bZIP in-frame AML)
Show evidence (1 reference)
PMID:38253683 SUPPORT Human Clinical
"Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf."
This supports WT1 and DNMT3A co-mutations as adverse modifiers in CEBPA bZIP in-frame AML.
FLT3-ITD (Adverse co-mutation in some CEBPA-mutated AML contexts)
Show evidence (1 reference)
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 FLT3-ITD as an adverse modifier in the normal karyotype CEBPA-mutated AML setting.
GATA2 (Co-mutation reported in CEBPA bZIP insertion-deletion AML)
Show evidence (1 reference)
PMID:38228680 SUPPORT Human Clinical
"Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS"
This pooled cohort explicitly names GATA2 among co-mutations observed in CEBPA bZIP insertion-deletion AML; the same sentence notes no independent OS impact in that favorable subgroup.
💊

Treatments

3
Intensive Chemotherapy
Action: chemotherapy MAXO:0000647
Agent: cytarabine ↗ daunorubicin ↗
Fit patients are commonly treated with intensive induction chemotherapy based on cytarabine plus an anthracycline, followed by consolidation. CEBPA-mutated AML trials are evaluating optimization of cytarabine-containing regimens.
Show evidence (1 reference)
clinicaltrials:NCT06529250 SUPPORT Human Clinical
"At present, the "3+7" treatment induction regimen of cytarabine combined with anthracyclines is still the first-line recommended regimen."
This trial summary supports cytarabine plus anthracycline induction as the referenced treatment backbone in CEBPA double-mutated AML.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
Allogeneic hematopoietic stem cell transplantation may be considered for high-relapse-risk AML-CEBPA patients after induction and consolidation or when MRD and molecular features indicate excess relapse risk.
Show evidence (1 reference)
clinicaltrials:NCT06458257 SUPPORT Human Clinical
"For newly diagnosed high-relapse-risk CEBPA mutant acute myeloid leukemia patients, we aim to perform allogeneic hematopoietic stem cell transplantation after patients finished one cycle of induction and two cycles of consolidation."
This clinical-trial summary supports transplant investigation in newly diagnosed high-relapse-risk CEBPA-mutated AML.
Supportive Care for Cytopenias and Infection Risk
Action: supportive care MAXO:0000950
Supportive care includes transfusion support, antimicrobial management, and monitoring for complications of marrow failure and chemotherapy-induced cytopenias.
🔬

Biochemical Markers

2
CEBPA Mutation Detection
Show evidence (1 reference)
PMID:37261703 SUPPORT Other
"Due to the recent advances in molecular testing and the prognostic role of CEBPA mutation in AML, the definition for AML with CEBPA mutation (AML-CEBPA) has significantly changed."
This review supports the importance of molecular testing and CEBPA mutation status for defining AML-CEBPA.
Minimal Residual Disease Assessment
Show evidence (1 reference)
PMID:37261703 SUPPORT Other
"In addition, minimal residual disease assessment post therapy to stratify disease risk and stem cell transplant in selected AML-CEBPA patients are discussed."
The review directly links MRD assessment to post-therapy risk stratification and transplant decisions for AML-CEBPA.
🔬

Clinical Trials

3
NCT06458257 NOT_APPLICABLE RECRUITING
Observational study evaluating allogeneic hematopoietic stem cell transplantation after induction and consolidation for newly diagnosed high-relapse-risk CEBPA-mutant AML.
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 trial summary states the transplant-oriented outcome measures in high-relapse-risk CEBPA-mutant AML.
NCT06529250 NOT_APPLICABLE RECRUITING
Multicenter randomized controlled trial testing intermediate-dose HAD regimen for CEBPA double-mutated AML.
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 a randomized evaluation of intermediate-dose HAD in CEBPA double-mutated AML.
NCT04415008 PHASE_II ACTIVE_NOT_RECRUITING
Prospective multicenter phase 2 study evaluating HAD induction with intensified cytarabine in newly diagnosed CEBPA double-mutated AML.
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 trial summary states the intensified HAD rationale for newly diagnosed CEBPA double-mutated AML.
{ }

Source YAML

click to show 
name: Acute Myeloid Leukemia with CEBPA Somatic Mutations
creation_date: "2026-05-11T12:14:38Z"
updated_date: "2026-05-11T16:45:00Z"
description: >-
  Acute myeloid leukemia with CEBPA somatic mutations is a molecularly defined
  AML subtype driven by acquired CEBPA alterations, especially bZIP in-frame
  mutations that define a favorable-risk genetic entity in current AML
  classifications. CEBPA encodes a myeloid transcription factor required for
  granulocytic differentiation; pathogenic disruption produces impaired myeloid
  maturation, blast accumulation in blood and marrow, and cytopenia-related
  complications. Outcomes are heterogeneous and are modified by mutation
  location, allelic state, and co-mutations such as WT1, DNMT3A, FLT3-ITD, and
  chromatin/cohesin/splicing gene lesions.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
has_subtypes:
- name: CEBPA bZIP In-Frame AML
  display_name: AML with CEBPA bZIP in-frame mutation
  description: >-
    AML with in-frame mutations in the C-terminal basic leucine zipper region of
    CEBPA. This subgroup corresponds to the most consistently favorable-risk
    CEBPA-mutated AML group, though adverse co-mutation patterns and immune or
    metabolic transcriptional programs can identify higher-relapse-risk cases.
  subtype_frequency: "Approximately 5-6% of intensively treated AML in recent cohorts"
  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: >-
      This pooled adult AML cohort supports bZIP in-frame/insertion-deletion
      mutations as the favorable CEBPA-mutated subgroup.
- name: Other CEBPA-Mutated AML
  description: >-
    CEBPA-mutated AML without the favorable bZIP in-frame pattern, including
    non-bZIP, bZIP stop, bZIP missense, or TAD-only mutation patterns. These
    cases may not share the same favorable prognosis and require risk
    stratification using the broader AML molecular context.
  evidence:
  - reference: PMID:37680323
    reference_title: "Location, location, location: A mini-review of CEBPA variants in patients with acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Whereas prior iterations did not specify the type of CEBPA mutation, the
      updated schema specify that only mutations localized to the C-terminal
      basic zipper (bZIP) domain are considered prognostically favorable.
    explanation: >-
      This review explains why mutation location distinguishes favorable bZIP
      disease from other CEBPA-mutated AML patterns.
pathophysiology:
- name: CEBPA Transcription Factor Disruption
  description: >-
    Somatic CEBPA mutations disrupt the activity of CCAAT/enhancer-binding
    protein alpha, a transcription factor that maintains the balance between
    myeloid progenitor proliferation and differentiation. Pathogenic disruption
    weakens the normal transcriptional program needed for granulocytic
    maturation.
  evidence:
  - reference: PMID:37621152
    reference_title: "Mutations in the bZip region of the CEBPA gene: A novel prognostic factor in patients with acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among them, the CCAAT-enhancer-binding protein alpha (CEBPA) plays a
      crucial role in maintaining the balance between myeloid proliferation and
      differentiation.
    explanation: >-
      This supports CEBPA as the transcription factor whose disruption alters
      the proliferation-differentiation balance in myeloid cells.
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: myeloid cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030099
      label: myeloid cell differentiation
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    modifier: DECREASED
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  gene_products:
  - preferred_term: CCAAT/enhancer binding protein alpha
    term:
      id: NCIT:C45488
      label: CCAAT/Enhancer Binding Protein Alpha
  downstream:
  - target: Myeloid Differentiation Block
    description: Impaired CEBPA activity prevents normal granulocytic maturation.
- name: Myeloid Differentiation Block
  description: >-
    Impaired CEBPA-mediated transcription favors arrested myeloid maturation.
    Immature blasts persist in an undifferentiated state and begin to accumulate
    in marrow and peripheral blood.
  evidence:
  - reference: PMID:37621152
    reference_title: "Mutations in the bZip region of the CEBPA gene: A novel prognostic factor in patients with acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imbalances in this network can lead to disrupted differentiation and
      contribute to the development of malignant diseases.
    explanation: >-
      The abstract links CEBPA transcription-factor network imbalance to
      disrupted differentiation in malignant hematologic disease.
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: negative regulation of cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045596
      label: negative regulation of cell differentiation
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Bone Marrow and Blood Blast Accumulation
    description: Arrested myeloblasts expand and replace normal hematopoiesis.
- name: Bone Marrow and Blood Blast Accumulation
  description: >-
    Leukemic myeloblasts accumulate in bone marrow and may circulate in blood,
    meeting the morphologic framework of AML and suppressing normal erythroid,
    granulocytic, and megakaryocytic output.
  evidence:
  - reference: PMID:23590662
    reference_title: "Acute myeloid leukemia: advances in diagnosis and classification."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by
      ≥20% myeloblasts in the blood or bone marrow.
    explanation: >-
      This AML diagnostic review supports the core blast-accumulation feature in
      blood or bone marrow.
  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
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Bone Marrow Failure
    description: Blast expansion suppresses normal hematopoiesis and causes cytopenias.
- name: Bone Marrow Failure
  description: >-
    Marrow replacement by leukemic blasts produces anemia, thrombocytopenia, and
    neutropenia, causing fatigue, bleeding, and infection susceptibility.
  evidence:
  - reference: PMID:37769139
    reference_title: "[Pancytopenia associated to acute myeloid leukemia: a case report of aleukemic leukemia]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow aspirate showed infiltration by 45% of myeloblasts and
      myelodysplasia.
    explanation: >-
      This AML case report supports marrow infiltration by myeloblasts as the
      substrate for marrow-failure presentation.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Cytopenia-Associated Complications
    description: Reduced mature blood-cell production causes AML presentation symptoms.
- name: Cytopenia-Associated Complications
  description: >-
    Cytopenias from marrow failure cause the major presenting complications of
    AML, including pancytopenia, fatigue from anemia, bleeding from
    thrombocytopenia, and infection risk from neutropenia.
  evidence:
  - reference: PMID:37769139
    reference_title: "[Pancytopenia associated to acute myeloid leukemia: a case report of aleukemic leukemia]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AML that is presented as pancytopenia should be considered in the
      evaluation of marrow failure syndrome.
    explanation: >-
      This case-report abstract directly links AML pancytopenia presentation to
      marrow failure evaluation.
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
- name: IFN and Metabolic Transcriptomic Risk Program
  description: >-
    Within CEBPA bZIP in-frame AML, some patients show immune and metabolic
    transcriptional programs associated with shorter event-free survival,
    including interferon-stimulated gene expression and mitochondrial complex
    gene overexpression.
  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 immune and metabolic pathway activation as a prognostic
      transcriptomic program in this subtype.
  biological_processes:
  - preferred_term: immune response
    modifier: INCREASED
    term:
      id: GO:0006955
      label: immune response
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
- name: CEBPA-Dependent Hematopoietic Progenitor Maintenance
  description: >-
    Model-organism evidence supports a conserved role for Cebpa in hematopoietic
    stem and progenitor cell generation, maintenance, and myeloid
    differentiation, providing mechanistic context for how CEBPA dysfunction can
    disturb blood-cell development.
  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: >-
      The CCAAT enhancer binding protein alpha (CEBPA) is crucial for myeloid
      differentiation and the balance of haematopoietic stem and progenitor cell
      (HSPC) quiescence and self-renewal, and its dysfunction can drive
      leukemogenesis.
    explanation: >-
      This zebrafish study supports the conserved developmental role of Cebpa in
      hematopoietic progenitors and leukemogenesis.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: myeloid cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030099
      label: myeloid cell differentiation
histopathology:
- name: Myeloblast Predominance
  finding_term:
    preferred_term: Myeloblasts present
    term:
      id: NCIT:C155995
      label: Myeloblasts Present
  frequency: VERY_FREQUENT
  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:23590662
    reference_title: "Acute myeloid leukemia: advances in diagnosis and classification."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by
      ≥20% myeloblasts in the blood or bone marrow.
    explanation: >-
      This supports the leukemia phenotype as a myeloid neoplasm with blood or
      marrow myeloblast accumulation.
- 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
- 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
- category: Hematologic
  name: Thrombocytopenia
  description: Reduced platelet production contributes to bruising and bleeding.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- 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
- 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
- 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
- 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
- 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
- category: Extramedullary
  name: Splenomegaly
  description: >-
    Splenic enlargement can occur when AML has extramedullary organ involvement,
    though it is not required for CEBPA-mutated AML diagnosis.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
- category: Extramedullary
  name: Hepatomegaly
  description: >-
    Hepatic enlargement can occur when AML has extramedullary organ involvement,
    though it is not required for CEBPA-mutated AML diagnosis.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
biochemical:
- name: CEBPA Mutation Detection
  biomarker_term:
    preferred_term: CEBPA gene mutation
    term:
      id: NCIT:C38372
      label: CEBPA Gene Mutation
  notes: >-
    CEBPA sequencing is required to classify this AML subtype, identify bZIP
    in-frame mutations, and distinguish favorable-risk from non-favorable CEBPA
    mutational patterns.
  evidence:
  - reference: PMID:37261703
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Due to the recent advances in molecular testing and the prognostic role of
      CEBPA mutation in AML, the definition for AML with CEBPA mutation
      (AML-CEBPA) has significantly changed.
    explanation: >-
      This review supports the importance of molecular testing and CEBPA mutation
      status for defining AML-CEBPA.
- name: Minimal Residual Disease Assessment
  notes: >-
    Post-therapy MRD assessment is used to stratify residual disease risk and
    inform transplant consideration in selected AML-CEBPA patients.
  evidence:
  - reference: PMID:37261703
    reference_title: Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, minimal residual disease assessment post therapy to stratify
      disease risk and stem cell transplant in selected AML-CEBPA patients are
      discussed.
    explanation: >-
      The review directly links MRD assessment to post-therapy risk
      stratification and transplant decisions for AML-CEBPA.
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
  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.
  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: Adverse co-mutation in CEBPA bZIP in-frame AML
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  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 supports WT1 and DNMT3A co-mutations as adverse modifiers in CEBPA
      bZIP in-frame AML.
- name: DNMT3A
  gene_term:
    preferred_term: DNMT3A
    term:
      id: hgnc:2978
      label: DNMT3A
  association: Adverse co-mutation in CEBPA bZIP in-frame AML
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  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 supports WT1 and DNMT3A co-mutations as adverse modifiers in CEBPA
      bZIP in-frame AML.
- name: FLT3-ITD
  gene_term:
    preferred_term: FLT3
    term:
      id: hgnc:3765
      label: FLT3
  association: Adverse co-mutation in some CEBPA-mutated AML contexts
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  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 FLT3-ITD as an adverse modifier in the normal
      karyotype CEBPA-mutated AML setting.
- name: GATA2
  gene_term:
    preferred_term: GATA2
    term:
      id: hgnc:4171
      label: GATA2
  association: Co-mutation reported in CEBPA bZIP insertion-deletion AML
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as
      well as ELN2022 adverse risk aberrations) had no independent impact on OS
    explanation: >-
      This pooled cohort explicitly names GATA2 among co-mutations observed in
      CEBPA bZIP insertion-deletion AML; the same sentence notes no independent
      OS impact in that favorable subgroup.
progression:
- phase: Diagnosis and Risk Stratification
  notes: >-
    Diagnosis combines AML blast criteria with molecular identification of CEBPA
    mutation location, allelic state, and co-mutations. bZIP in-frame CEBPA
    disease is generally favorable-risk, but co-mutation and transcriptomic
    risk patterns can identify higher-risk cases.
  evidence:
  - reference: PMID:37120689
    reference_title: "AML classification in the year 2023: How to avoid a Babylonian confusion of languages."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, both classifications focus on more genetics-based
      definitions with similar basic concepts and a large degree of agreement.
    explanation: >-
      This supports genetics-based classification as the diagnostic framework
      for AML entities including AML-CEBPA.
- phase: Complete Remission and Relapse Risk
  notes: >-
    CEBPA bZIP in-frame/insertion-deletion AML has higher complete remission
    rates and longer relapse-free and overall survival than other CEBPA-mutated
    groups, but relapse risk persists and may be higher with adverse molecular
    features.
  evidence:
  - reference: PMID:38228680
    reference_title: Prognostic impact of CEBPA mutational subgroups in adult AML.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, these results demonstrate bZIPInDel mutations to be the
      major independent determinant of outcome in CEBPA-mutant AML, thereby
      refining current classifications according to WHO (including all dmCEBPA
      and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including
      CEBPA bZIPms).
    explanation: >-
      This pooled cohort supports mutation location as the dominant prognostic
      determinant for progression risk in CEBPA-mutant AML.
treatments:
- name: Intensive Chemotherapy
  description: >-
    Fit patients are commonly treated with intensive induction chemotherapy based
    on cytarabine plus an anthracycline, followed by consolidation. CEBPA-mutated
    AML trials are evaluating optimization of cytarabine-containing regimens.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
    - preferred_term: daunorubicin
      term:
        id: CHEBI:41977
        label: daunorubicin
  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: >-
      At present, the "3+7" treatment induction regimen of cytarabine combined
      with anthracyclines is still the first-line recommended regimen.
    explanation: >-
      This trial summary supports cytarabine plus anthracycline induction as the
      referenced treatment backbone in CEBPA double-mutated AML.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation may be considered for
    high-relapse-risk AML-CEBPA patients after induction and consolidation or
    when MRD and molecular features indicate excess relapse risk.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  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: >-
      For newly diagnosed high-relapse-risk CEBPA mutant acute myeloid leukemia
      patients, we aim to perform allogeneic hematopoietic stem cell
      transplantation after patients finished one cycle of induction and two
      cycles of consolidation.
    explanation: >-
      This clinical-trial summary supports transplant investigation in newly
      diagnosed high-relapse-risk CEBPA-mutated AML.
- name: Supportive Care for Cytopenias and Infection Risk
  description: >-
    Supportive care includes transfusion support, antimicrobial management, and
    monitoring for complications of marrow failure and chemotherapy-induced
    cytopenias.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
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: >-
    Observational study evaluating allogeneic hematopoietic stem cell
    transplantation after induction and consolidation for newly diagnosed
    high-relapse-risk CEBPA-mutant AML.
  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 trial summary states the transplant-oriented outcome measures in
      high-relapse-risk CEBPA-mutant AML.
- name: NCT06529250
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Multicenter randomized controlled trial testing intermediate-dose HAD
    regimen for CEBPA double-mutated AML.
  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 a randomized evaluation of intermediate-dose
      HAD in CEBPA double-mutated AML.
- name: NCT04415008
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Prospective multicenter phase 2 study evaluating HAD induction with
    intensified cytarabine in newly diagnosed CEBPA double-mutated AML.
  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 trial summary states the intensified HAD rationale for newly diagnosed
      CEBPA double-mutated AML.
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: hematologic malignancy
📚

References & Deep Research

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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