Acute Megakaryoblastic Leukemia

MONDO:0018872 Pathograph 7 acute myeloid leukemia

Acute megakaryoblastic leukemia (AMKL, FAB M7) is a rare subtype of acute myeloid leukemia in which the malignant blasts commit to the megakaryocytic lineage. AMKL accounts for less than 5% of adult AML but 4-15% of pediatric AML, and arises in two clinically and mechanistically distinct contexts. Down syndrome-associated myeloid leukemia (ML-DS) is driven by trisomy 21 plus acquired GATA1 truncating mutations evolving from transient abnormal myelopoiesis (TAM); non-Down syndrome AMKL is dominated in infants by the RBM15-MKL1 t(1;22) fusion and by recurrent CBFA2T3-GLIS2 and NUP98 rearrangements in older children. Both contexts converge on a block of terminal megakaryocyte differentiation with aberrant megakaryoblast self-renewal and bone marrow fibrosis.

Ask OpenScientist

Ask a research question about Acute Megakaryoblastic Leukemia. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

0
Mappings
0
Definitions
0
Inheritance
7
Pathophysiology
2
Histopathology
11
Phenotypes
7
Pathograph
8
Genes
4
Treatments
5
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
1
Deep Research
🏷

Classifications

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

Subtypes

5
Myeloid Leukemia of Down Syndrome (ML-DS) MONDO:0850271
AMKL arising in children with constitutional trisomy 21, typically preceded by transient abnormal myelopoiesis (TAM) in the neonatal period. Driven by acquired N-terminal truncating mutations in GATA1 producing the short GATA1s isoform on a trisomy 21 background. Has favorable response to reduced-intensity cytarabine-based chemotherapy.
Non-Down Syndrome Infant AMKL with t(1;22) RBM15-MKL1 MONDO:0018436
AMKL of infants and very young children without Down syndrome, classically defined by the t(1;22)(p13;q13) translocation creating the RBM15-MKL1 (also called OTT-MAL) fusion. Presents with marked organomegaly and bone marrow fibrosis.
CBFA2T3-GLIS2 Pediatric AMKL MONDO:0975868
Pediatric non-Down AMKL defined by the cryptic inv(16)(p13.3q24.3) fusing CBFA2T3 to GLIS2. Activates Hedgehog and BMP signaling, confers very poor prognosis, and is the most common recurrent fusion in non-Down pediatric AMKL.
NUP98-rearranged Pediatric AMKL
Pediatric AMKL with NUP98 fusions, most commonly NUP98-KDM5A (also reported NUP98-NSD1, NUP98-BPTF). NUP98 fusions deregulate HOX gene expression and are associated with high relapse risk.
HOX-rearranged Pediatric Non-DS AMKL
Pediatric non-DS AMKL defined by heterogeneous fusions involving HOX cluster genes (e.g., EWSR1-HOXB8, EP300-HOXA7, NIPBL-HOXB9, GATA2-HOXA10), accounting for ~14% of pediatric non-DS-AMKL with shared HOX gene expression program, frequent cooperating activating MPL mutations, and superior outcomes similar to RBM15-MKL1 cases.
Show evidence (2 references)
PMID:28112737 SUPPORT Human Clinical
"Collectively, fusions involving a HOX cluster gene (HOXr) occurred in 14% of patients within this cohort"
Defines the HOXr subgroup and quantifies its share of pediatric non-DS AMKL.
PMID:28112737 SUPPORT Human Clinical
"GATA1 and HOXr subgroups carried significantly superior outcomes"
Establishes that the HOXr subgroup has favorable clinical outcomes, similar to RBM15-MKL1 cases.
⚙

Pathophysiology

7
Megakaryocytic Lineage Commitment with Differentiation Block
AMKL blasts arise from immature hematopoietic progenitors that commit to the megakaryocyte/erythroid lineage but fail to undergo terminal megakaryocyte maturation. Whether the founding lesion is GATA1s in trisomy 21 or a non-DS chimeric oncogene, the shared output is accumulation of immature, often dysmorphic megakaryoblasts with retained self-renewal and expression of platelet/megakaryocyte markers (CD41, CD42, CD61).
megakaryocyte progenitor cell link megakaryocyte-erythroid progenitor cell link
megakaryocyte differentiation link ↓ DECREASED
Downstream
Megakaryoblast Accumulation and Marrow Failure Differentiation block plus retained proliferation drives megakaryoblast accumulation in bone marrow.
Show evidence (2 references)
PMID:8069184 SUPPORT Human Clinical
"The target cells of AMKL and TAM are immature cells close to stem cells which are capable of differentiating into lineage cells such as megakaryocytes, erythrocytes and myeloid cells."
Establishes that AMKL/TAM blasts are immature MEP-like progenitors with megakaryocytic differentiation potential.
PMID:26186939 SUPPORT Human Clinical
"Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of newly diagnosed pediatric acute myeloid leukemia patients."
Frames pediatric AMKL as a defined subset of AML, supporting megakaryocytic-lineage classification.
GATA1s Truncation in Trisomy 21 (ML-DS)
In ML-DS, somatic mutations in GATA1 introduce premature stop codons in the N-terminal activation domain (exon 2). This abrogates production of full-length GATA1 but preserves expression of a shorter, internally initiated isoform, GATA1s, that retains DNA binding and FOG1 interaction but has reduced transactivation. Acting on a fetal liver/yolk sac progenitor with trisomy 21, GATA1s drives the transient abnormal myelopoiesis (TAM) phenotype in neonates; in ~10-20% of TAM cases, additional cooperating mutations transform TAM into overt ML-DS. GATA1 mutations are detected in essentially every TAM and ML-DS case but are not seen in non-DS AMKL.
megakaryocyte progenitor cell link
megakaryocyte differentiation link ↓ DECREASED hematopoietic stem cell proliferation link ↑ INCREASED
Downstream
Megakaryoblast Accumulation and Marrow Failure GATA1s plus trisomy 21 supports clonal megakaryoblast expansion that, with cooperating mutations, evolves to overt ML-DS.
Show evidence (4 references)
PMID:12172547 SUPPORT Human Clinical
"leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1"
Establishes near-universal GATA1 mutation in DS-AMKL, the founding lesion of ML-DS.
PMID:12172547 SUPPORT Human Clinical
"Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream."
Defines the molecular consequence of GATA1 truncating mutations - loss of full-length GATA1 with preservation of GATA1s.
PMID:14636651 SUPPORT Human Clinical
"We detected GATA1 mutations in TMD blasts from every infant examined."
Documents GATA1 mutations as initiating lesions in transient myeloproliferative disorder (TAM/TMD), the precursor to ML-DS.
+ 1 more reference
RBM15-MKL1 Fusion Oncogene (Infant AMKL)
The t(1;22)(p13;q13) translocation fuses RBM15 (also called OTT) on chromosome 1 with MKL1 (MRTFA, also called MAL) on chromosome 22, creating the RBM15-MKL1 (OTT-MAL) chimeric transcription cofactor. This fusion is essentially restricted to infants and young children with non-DS AMKL and drives megakaryocytic transformation by deregulating Notch and SRF/MAL transcriptional programs in early hematopoietic progenitors.
megakaryocyte progenitor cell link
Downstream
Megakaryoblast Accumulation and Marrow Failure RBM15-MKL1 fusion drives megakaryocytic differentiation block and clonal expansion of immature blasts.
Show evidence (2 references)
PMID:15849773 SUPPORT Human Clinical
"The t(1;22)(p13;q13) is a nonrandom chromosomal abnormality in acute leukemia with the fusion oncogene, RBM15-MKL1 (OTT-MAL), identified recently. However, this abnormality has been described only in infants and young children with acute megakaryoblastic leukemia (AMKL)."
Defines RBM15-MKL1 as the t(1;22) fusion oncogene and establishes its restriction to infant/young-child AMKL.
PMID:27114462 SUPPORT Human Clinical
"RBM15/MKL1-rearranged patients were significantly younger."
Confirms in a 153-patient pediatric AMKL cohort that RBM15-MKL1 cases occur in younger children (infants), consistent with its biology.
CBFA2T3-GLIS2 Fusion Activates BMP and Hedgehog Signaling
A cryptic chromosome 16 inversion, inv(16)(p13.3q24.3), fuses CBFA2T3 (ETO2) to the Hedgehog-pathway zinc finger transcription factor GLIS2. The CBFA2T3-GLIS2 fusion protein induces BMP signaling and confers enhanced self-renewal on hematopoietic progenitors, defining the most frequent and clinically aggressive recurrent oncogene of pediatric non-DS AMKL. The fusion is detected in approximately 16-27% of pediatric AMKL cases and predicts very poor outcome.
hematopoietic stem cell link megakaryocyte progenitor cell link
BMP signaling pathway link ↑ INCREASED stem cell population maintenance link ↑ INCREASED
Downstream
Megakaryoblast Accumulation and Marrow Failure BMP-driven self-renewal plus differentiation block produces megakaryoblast expansion.
Show evidence (3 references)
PMID:23153540 SUPPORT Human Clinical
"Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein."
Establishes CBFA2T3-GLIS2 as a cryptic inv(16) fusion in approximately 27% of pediatric AMKL.
PMID:23153540 SUPPORT Model Organism
"Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors."
Functional in vivo evidence that CBFA2T3-GLIS2 activates BMP signaling and enhances hematopoietic self-renewal.
PMID:26186939 SUPPORT Human Clinical
"CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in this subset of patients and confers a poor prognosis."
Frames CBFA2T3-GLIS2 as the dominant chimeric oncogene of non-DS pediatric AMKL with adverse prognosis.
NUP98 Fusion-Driven HOX Deregulation
NUP98 fusions in pediatric AMKL (most commonly NUP98-KDM5A; also NUP98-NSD1 and rare NUP98-BPTF) produce chromatin-modifying chimeric transcription factors that ectopically activate HOXA cluster gene expression in early progenitors, blocking differentiation and supporting self-renewal. NUP98-rearranged AMKL is associated with high relapse risk and poor outcome.
hematopoietic stem cell link
Downstream
Megakaryoblast Accumulation and Marrow Failure NUP98 fusion proteins maintain immature progenitor self-renewal and block megakaryocytic maturation.
Show evidence (2 references)
PMID:28112737 SUPPORT Human Clinical
"Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A."
Lists NUP98-KDM5A as one of the recurrent chimeric oncogenes defining non-DS-AMKL subgroups.
PMID:28063190 SUPPORT Human Clinical
"Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors."
Confirms NUP98-KDM5A as a poor-prognosis recurrent fusion in pediatric AMKL.
Cooperating Mutations in Kinase, Cohesin, and Cell-Cycle Pathways
Beyond the founding fusion oncogenes, pediatric non-DS-AMKL carries recurrent cooperating mutations whose enrichment is fusion-subgroup specific. RB1 deletion is nearly universal in NUP98-KDM5A AMKL and contributes to its aggressive phenotype. KMT2A-rearranged cases are enriched for RAS pathway lesions; HOX-rearranged cases show recurrent activating MPL mutations that supply JAK-STAT growth signaling cooperative with the HOX gene expression program; GATA1-mutant non-DS cases show enrichment of JAK pathway and cohesin/CTCF lesions. These cooperating lesions explain heterogeneous outcomes within fusion subgroups.
Downstream
Megakaryoblast Accumulation and Marrow Failure Cooperating kinase, cohesin, and cell-cycle lesions amplify the proliferation and survival defects driven by the founding fusion oncogene, contributing to overt leukemic transformation.
Show evidence (3 references)
PMID:28112737 SUPPORT Human Clinical
"the most highly recurrent mutations occurred in GATA1 (13.3%), JAK kinase or STAT genes (16.9%), Cohesin or CTCF genes (18.1%), and RAS pathway genes (15.7%)"
Quantifies the most recurrent cooperating SNV/Indel mutation classes in pediatric non-DS-AMKL.
PMID:28112737 SUPPORT Human Clinical
"NUP98-KDM5A cases carried mutations in RB1 almost without exception and demonstrated a decrease in expression of this gene"
Establishes RB1 loss as the near-universal cooperating lesion of NUP98-KDM5A AMKL.
PMID:28112737 SUPPORT Human Clinical
"HOXr cases were found to be significantly enriched in activating MPL mutations"
Supports cooperating activating MPL mutations as a feature of the HOXr AMKL subgroup, supplying JAK-STAT signaling cooperative with the HOX expression program.
Megakaryoblast Accumulation and Marrow Failure
Differentiation-blocked megakaryoblasts accumulate in the bone marrow, crowding out normal hematopoiesis. The accompanying release of megakaryocyte-derived cytokines (PDGF, TGF-beta) drives marrow stromal fibrosis, while cytopenias produce anemia, thrombocytopenia, and susceptibility to infection. In some patients leukemic cells circulate and infiltrate liver and spleen.
megakaryocyte link megakaryocyte progenitor cell link
bone marrow link
Show evidence (1 reference)
PMID:28112737 SUPPORT Human Clinical
"Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts."
Defines the morphologic hallmark of AMKL, marrow accumulation of abnormal megakaryoblasts.
✶

Histopathology

2
Megakaryoblast Predominance VERY_FREQUENT
Bone marrow shows infiltration by abnormal blasts with megakaryocytic features (cytoplasmic blebs, basophilic cytoplasm) expressing CD41/CD61 and often CD42b. Diagnosis requires a megakaryocytic immunophenotype on blasts comprising at least 20% of marrow cells (FAB M7 criteria).
Show evidence (1 reference)
PMID:28112737 SUPPORT Human Clinical
"Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts."
Establishes the defining morphologic finding of AMKL.
Marrow Reticulin Fibrosis FREQUENT
Megakaryoblast-derived growth factors (PDGF, TGF-beta) stimulate stromal fibroblasts to deposit reticulin fibers, producing the dense marrow fibrosis that often makes aspirate dry-tap and necessitates trephine biopsy for diagnosis. Particularly prominent in infant t(1;22) RBM15-MKL1 AMKL.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acute Megakaryoblastic Leukemia 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 5
Thrombocytopenia VERY_FREQUENT Thrombocytopenia (HP:0001873)
Anemia VERY_FREQUENT Anemia (HP:0001903)
Pancytopenia FREQUENT Pancytopenia (HP:0001876)
Bleeding Tendency FREQUENT Abnormal bleeding (HP:0001892)
Petechiae FREQUENT Petechiae (HP:0000967)
Cardiovascular 1
Hepatosplenomegaly OCCASIONAL Hepatosplenomegaly (HP:0001433)
Immune 1
Recurrent Infections FREQUENT Recurrent infections (HP:0002719)
Constitutional 1
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Other 3
Acute Megakaryocytic Leukemia VERY_FREQUENT Acute megakaryocytic leukemia (HP:0006733)
Increased Megakaryocyte Count VERY_FREQUENT Increased megakaryocyte count (HP:0005513)
Bone Marrow Fibrosis FREQUENT Myelofibrosis (HP:0011974)
🧬

Genetic Associations

8
GATA1 (Somatic Initiating Mutation (ML-DS))
Show evidence (1 reference)
PMID:12172547 SUPPORT Human Clinical
"leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1"
Establishes GATA1 mutation as the founding lesion of DS-AMKL.
RBM15 (Somatic Oncogenic Fusion Partner)
MRTFA (MKL1) (Somatic Oncogenic Fusion Partner)
CBFA2T3 (Somatic Oncogenic Fusion Partner)
GLIS2 (Somatic Oncogenic Fusion Partner)
Show evidence (1 reference)
PMID:23153540 SUPPORT Model Organism
"Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors."
Functional evidence that GLIS2 fused to CBFA2T3 induces BMP signaling and self-renewal.
NUP98 (Somatic Oncogenic Fusion Partner)
KDM5A (Somatic Oncogenic Fusion Partner)
KMT2A (Cooperating Rearrangement)
Show evidence (1 reference)
PMID:27114462 SUPPORT Human Clinical
"CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive."
Quantifies recurrent aberration frequencies in 153 pediatric AMKL cases and notes mutual exclusivity.
💊

Treatments

4
Reduced-Intensity Cytarabine-Based Chemotherapy (ML-DS)
Action: chemotherapy MAXO:0000647
Agent: cytarabine ↗
Children with ML-DS have superior outcomes on reduced-intensity AML regimens that lower etoposide dose and omit maintenance therapy. The international ML-DS 2006 trial showed 5-year overall survival approaching 90% with this approach, exploiting the heightened cytarabine sensitivity conferred by GATA1s and trisomy 21.
Show evidence (1 reference)
PMID:28400376 SUPPORT Human Clinical
"Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility."
Establishes the rationale for therapy reduction in ML-DS.
Intensive Pediatric AML Chemotherapy (Non-DS AMKL)
Action: chemotherapy MAXO:0000647
Non-DS AMKL is treated with full-intensity multi-agent AML induction (cytarabine plus anthracycline) and consolidation. Outcomes remain inferior to ML-DS, particularly for CBFA2T3-GLIS2 and NUP98-KDM5A subtypes, motivating risk-adapted protocols.
Show evidence (2 references)
PMID:28112737 SUPPORT Human Clinical
"Identification of key genomic events in newly diagnosed non-DS-AMKL patients is important for risk stratification as these lesions have therapeutic implications."
Supports the rationale for genomically risk-adapted intensive AML chemotherapy in non-DS pediatric AMKL.
PMID:27114462 SUPPORT Human Clinical
"We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring."
Supports tailoring of pediatric non-DS AMKL chemotherapy intensity based on genetic risk group.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
Allogeneic HSCT in first remission is considered for high-risk non-DS AMKL, particularly CBFA2T3-GLIS2-positive, NUP98-KDM5A-positive, KMT2A-rearranged, or monosomy 7 cases. Generally avoided in ML-DS, where chemotherapy alone produces excellent outcomes.
Show evidence (1 reference)
PMID:27114462 SUPPORT Human Clinical
"NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions."
Identifies the high-risk genetic subgroups for whom intensified therapy and HSCT consolidation are considered.
TAM Surveillance and Pre-emptive Low-Dose Cytarabine
Action: chemotherapy MAXO:0000647
Agent: cytarabine ↗
DS neonates with transient abnormal myelopoiesis (TAM) are monitored for progression to ML-DS; symptomatic TAM with hyperleukocytosis, hepatosplenomegaly, or hepatic dysfunction may receive low-dose cytarabine to reduce mortality and progression risk.
Show evidence (1 reference)
PMID:14636651 SUPPORT Human Clinical
"TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients."
Justifies TAM surveillance given TAM frequency in DS newborns and substantial progression rate to AMKL.
🔬

Biochemical Markers

4
Megakaryocytic Immunophenotyping
Cytogenetic and FISH Analysis
GATA1 Sequencing in DS
RT-PCR for Recurrent Fusions
{ }

Source YAML

click to show 
name: Acute Megakaryoblastic Leukemia
creation_date: "2026-05-08T12:00:00Z"
updated_date: "2026-05-08T18:00:00Z"
description: >-
  Acute megakaryoblastic leukemia (AMKL, FAB M7) is a rare subtype of acute
  myeloid leukemia in which the malignant blasts commit to the megakaryocytic
  lineage. AMKL accounts for less than 5% of adult AML but 4-15% of pediatric
  AML, and arises in two clinically and mechanistically distinct contexts.
  Down syndrome-associated myeloid leukemia (ML-DS) is driven by trisomy 21
  plus acquired GATA1 truncating mutations evolving from transient abnormal
  myelopoiesis (TAM); non-Down syndrome AMKL is dominated in infants by the
  RBM15-MKL1 t(1;22) fusion and by recurrent CBFA2T3-GLIS2 and NUP98
  rearrangements in older children. Both contexts converge on a block of
  terminal megakaryocyte differentiation with aberrant megakaryoblast
  self-renewal and bone marrow fibrosis.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Pediatric Cancer
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
disease_term:
  preferred_term: acute megakaryoblastic leukemia
  term:
    id: MONDO:0018872
    label: acute megakaryoblastic leukemia
has_subtypes:
- name: ML-DS
  display_name: Myeloid Leukemia of Down Syndrome (ML-DS)
  description: >-
    AMKL arising in children with constitutional trisomy 21, typically preceded
    by transient abnormal myelopoiesis (TAM) in the neonatal period. Driven by
    acquired N-terminal truncating mutations in GATA1 producing the short
    GATA1s isoform on a trisomy 21 background. Has favorable response to
    reduced-intensity cytarabine-based chemotherapy.
  subtype_term:
    preferred_term: myeloid leukemia associated with Down syndrome
    term:
      id: MONDO:0850271
      label: myeloid leukemia associated with down syndrome
- name: Non-Down Infant AMKL
  display_name: Non-Down Syndrome Infant AMKL with t(1;22) RBM15-MKL1
  description: >-
    AMKL of infants and very young children without Down syndrome, classically
    defined by the t(1;22)(p13;q13) translocation creating the RBM15-MKL1
    (also called OTT-MAL) fusion. Presents with marked organomegaly and bone
    marrow fibrosis.
  subtype_term:
    preferred_term: megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)
    term:
      id: MONDO:0018436
      label: megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)
- name: CBFA2T3-GLIS2 AMKL
  display_name: CBFA2T3-GLIS2 Pediatric AMKL
  description: >-
    Pediatric non-Down AMKL defined by the cryptic inv(16)(p13.3q24.3) fusing
    CBFA2T3 to GLIS2. Activates Hedgehog and BMP signaling, confers very poor
    prognosis, and is the most common recurrent fusion in non-Down pediatric
    AMKL.
  subtype_term:
    preferred_term: acute myeloid leukemia with CBFA2T3-GLIS2 fusion
    term:
      id: MONDO:0975868
      label: acute myeloid leukemia with CBFA2T3-GLIS2 fusion
- name: NUP98-rearranged AMKL
  display_name: NUP98-rearranged Pediatric AMKL
  description: >-
    Pediatric AMKL with NUP98 fusions, most commonly NUP98-KDM5A (also reported
    NUP98-NSD1, NUP98-BPTF). NUP98 fusions deregulate HOX gene expression and
    are associated with high relapse risk.
- name: HOXr AMKL
  display_name: HOX-rearranged Pediatric Non-DS AMKL
  description: >-
    Pediatric non-DS AMKL defined by heterogeneous fusions involving HOX cluster
    genes (e.g., EWSR1-HOXB8, EP300-HOXA7, NIPBL-HOXB9, GATA2-HOXA10), accounting
    for ~14% of pediatric non-DS-AMKL with shared HOX gene expression program,
    frequent cooperating activating MPL mutations, and superior outcomes
    similar to RBM15-MKL1 cases.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, fusions involving a HOX cluster gene (HOXr) occurred in 14%
      of patients within this cohort
    explanation: >-
      Defines the HOXr subgroup and quantifies its share of pediatric non-DS
      AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GATA1 and HOXr subgroups carried significantly superior outcomes
    explanation: >-
      Establishes that the HOXr subgroup has favorable clinical outcomes,
      similar to RBM15-MKL1 cases.
pathophysiology:
- name: Megakaryocytic Lineage Commitment with Differentiation Block
  description: >-
    AMKL blasts arise from immature hematopoietic progenitors that commit to
    the megakaryocyte/erythroid lineage but fail to undergo terminal
    megakaryocyte maturation. Whether the founding lesion is GATA1s in trisomy
    21 or a non-DS chimeric oncogene, the shared output is accumulation of
    immature, often dysmorphic megakaryoblasts with retained self-renewal and
    expression of platelet/megakaryocyte markers (CD41, CD42, CD61).
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  - preferred_term: megakaryocyte-erythroid progenitor cell
    term:
      id: CL:0000050
      label: megakaryocyte-erythroid progenitor cell
  biological_processes:
  - preferred_term: megakaryocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030219
      label: megakaryocyte differentiation
  evidence:
  - reference: PMID:8069184
    reference_title: "Phenotypic characteristics of acute megakaryocytic leukemia and transient abnormal myelopoiesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The target cells of AMKL and TAM are immature cells close to stem cells
      which are capable of differentiating into lineage cells such as
      megakaryocytes, erythrocytes and myeloid cells.
    explanation: >-
      Establishes that AMKL/TAM blasts are immature MEP-like progenitors with
      megakaryocytic differentiation potential.
  - reference: PMID:26186939
    reference_title: "The biology of pediatric acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of
      newly diagnosed pediatric acute myeloid leukemia patients.
    explanation: >-
      Frames pediatric AMKL as a defined subset of AML, supporting
      megakaryocytic-lineage classification.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      Differentiation block plus retained proliferation drives megakaryoblast
      accumulation in bone marrow.
- name: GATA1s Truncation in Trisomy 21 (ML-DS)
  description: >-
    In ML-DS, somatic mutations in GATA1 introduce premature stop codons in
    the N-terminal activation domain (exon 2). This abrogates production of
    full-length GATA1 but preserves expression of a shorter, internally
    initiated isoform, GATA1s, that retains DNA binding and FOG1 interaction
    but has reduced transactivation. Acting on a fetal liver/yolk sac
    progenitor with trisomy 21, GATA1s drives the transient abnormal
    myelopoiesis (TAM) phenotype in neonates; in ~10-20% of TAM cases,
    additional cooperating mutations transform TAM into overt ML-DS. GATA1
    mutations are detected in essentially every TAM and ML-DS case but are
    not seen in non-DS AMKL.
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  biological_processes:
  - preferred_term: megakaryocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030219
      label: megakaryocyte differentiation
  - preferred_term: hematopoietic stem cell proliferation
    modifier: INCREASED
    term:
      id: GO:0071425
      label: hematopoietic stem cell proliferation
  evidence:
  - reference: PMID:12172547
    reference_title: "Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukemic cells from every individual with DS-AMKL that we examined
      contain mutations in GATA1
    explanation: >-
      Establishes near-universal GATA1 mutation in DS-AMKL, the founding
      lesion of ML-DS.
  - reference: PMID:12172547
    reference_title: "Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each mutation results in the introduction of a premature stop codon in
      the gene sequence that encodes the amino-terminal activation domain.
      These mutations prevent synthesis of full-length GATA1, but not
      synthesis of a shorter variant that is initiated downstream.
    explanation: >-
      Defines the molecular consequence of GATA1 truncating mutations - loss
      of full-length GATA1 with preservation of GATA1s.
  - reference: PMID:14636651
    reference_title: "Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected GATA1 mutations in TMD blasts from every infant examined.
    explanation: >-
      Documents GATA1 mutations as initiating lesions in transient
      myeloproliferative disorder (TAM/TMD), the precursor to ML-DS.
  - reference: PMID:14636651
    reference_title: "Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TMD is a common myeloid disorder that affects 10% of DS newborns and
      evolves to AMKL in nearly 30% patients.
    explanation: >-
      Quantifies TAM incidence in DS newborns and progression rate to AMKL.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      GATA1s plus trisomy 21 supports clonal megakaryoblast expansion that,
      with cooperating mutations, evolves to overt ML-DS.
- name: RBM15-MKL1 Fusion Oncogene (Infant AMKL)
  description: >-
    The t(1;22)(p13;q13) translocation fuses RBM15 (also called OTT) on
    chromosome 1 with MKL1 (MRTFA, also called MAL) on chromosome 22, creating
    the RBM15-MKL1 (OTT-MAL) chimeric transcription cofactor. This fusion is
    essentially restricted to infants and young children with non-DS AMKL and
    drives megakaryocytic transformation by deregulating Notch and SRF/MAL
    transcriptional programs in early hematopoietic progenitors.
  cell_types:
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  gene_products:
  - preferred_term: RBM15-MKL1 fusion protein
    term:
      id: NCIT:C99702
      label: RBM15/MKL1 Fusion Protein
  evidence:
  - reference: PMID:15849773
    reference_title: "RBM15-MKL1 (OTT-MAL) fusion transcript in an adult acute myeloid leukemia patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The t(1;22)(p13;q13) is a nonrandom chromosomal abnormality in acute
      leukemia with the fusion oncogene, RBM15-MKL1 (OTT-MAL), identified
      recently. However, this abnormality has been described only in infants
      and young children with acute megakaryoblastic leukemia (AMKL).
    explanation: >-
      Defines RBM15-MKL1 as the t(1;22) fusion oncogene and establishes its
      restriction to infant/young-child AMKL.
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBM15/MKL1-rearranged patients were significantly younger.
    explanation: >-
      Confirms in a 153-patient pediatric AMKL cohort that RBM15-MKL1 cases
      occur in younger children (infants), consistent with its biology.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      RBM15-MKL1 fusion drives megakaryocytic differentiation block and clonal
      expansion of immature blasts.
- name: CBFA2T3-GLIS2 Fusion Activates BMP and Hedgehog Signaling
  description: >-
    A cryptic chromosome 16 inversion, inv(16)(p13.3q24.3), fuses CBFA2T3
    (ETO2) to the Hedgehog-pathway zinc finger transcription factor GLIS2.
    The CBFA2T3-GLIS2 fusion protein induces BMP signaling and confers
    enhanced self-renewal on hematopoietic progenitors, defining the most
    frequent and clinically aggressive recurrent oncogene of pediatric
    non-DS AMKL. The fusion is detected in approximately 16-27% of pediatric
    AMKL cases and predicts very poor outcome.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  biological_processes:
  - preferred_term: BMP signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  - preferred_term: stem cell population maintenance
    modifier: INCREASED
    term:
      id: GO:0019827
      label: stem cell population maintenance
  gene_products:
  - preferred_term: CBFA2T3-GLIS2 fusion protein
    term:
      id: NCIT:C105820
      label: CBFA2T3/GLIS2 Fusion Protein
  evidence:
  - reference: PMID:23153540
    reference_title: "An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis identified a cryptic chromosome 16 inversion
      (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a
      CBFA2T3-GLIS2 fusion protein.
    explanation: >-
      Establishes CBFA2T3-GLIS2 as a cryptic inv(16) fusion in approximately
      27% of pediatric AMKL.
  - reference: PMID:23153540
    reference_title: "An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic
      cells induced bone morphogenic protein (BMP) signaling and resulted in
      a marked increase in the self-renewal capacity of hematopoietic
      progenitors.
    explanation: >-
      Functional in vivo evidence that CBFA2T3-GLIS2 activates BMP signaling
      and enhances hematopoietic self-renewal.
  - reference: PMID:26186939
    reference_title: "The biology of pediatric acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date
      in this subset of patients and confers a poor prognosis.
    explanation: >-
      Frames CBFA2T3-GLIS2 as the dominant chimeric oncogene of non-DS
      pediatric AMKL with adverse prognosis.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      BMP-driven self-renewal plus differentiation block produces
      megakaryoblast expansion.
- name: NUP98 Fusion-Driven HOX Deregulation
  description: >-
    NUP98 fusions in pediatric AMKL (most commonly NUP98-KDM5A; also
    NUP98-NSD1 and rare NUP98-BPTF) produce chromatin-modifying chimeric
    transcription factors that ectopically activate HOXA cluster gene
    expression in early progenitors, blocking differentiation and supporting
    self-renewal. NUP98-rearranged AMKL is associated with high relapse risk
    and poor outcome.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  gene_products:
  - preferred_term: NUP98-KDM5A fusion protein
    term:
      id: NCIT:C105816
      label: NUP98/KDM5A Fusion Protein
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous efforts have identified chimeric oncogenes in a substantial
      number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A
      gene rearrangements, and NUP98-KDM5A.
    explanation: >-
      Lists NUP98-KDM5A as one of the recurrent chimeric oncogenes defining
      non-DS-AMKL subgroups.
  - reference: PMID:28063190
    reference_title: "Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL
      were recently reported as poor prognostic factors.
    explanation: >-
      Confirms NUP98-KDM5A as a poor-prognosis recurrent fusion in pediatric
      AMKL.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      NUP98 fusion proteins maintain immature progenitor self-renewal and
      block megakaryocytic maturation.
- name: Cooperating Mutations in Kinase, Cohesin, and Cell-Cycle Pathways
  description: >-
    Beyond the founding fusion oncogenes, pediatric non-DS-AMKL carries
    recurrent cooperating mutations whose enrichment is fusion-subgroup
    specific. RB1 deletion is nearly universal in NUP98-KDM5A AMKL and
    contributes to its aggressive phenotype. KMT2A-rearranged cases are
    enriched for RAS pathway lesions; HOX-rearranged cases show recurrent
    activating MPL mutations that supply JAK-STAT growth signaling cooperative
    with the HOX gene expression program; GATA1-mutant non-DS cases show
    enrichment of JAK pathway and cohesin/CTCF lesions. These cooperating
    lesions explain heterogeneous outcomes within fusion subgroups.
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most highly recurrent mutations occurred in GATA1 (13.3%), JAK kinase
      or STAT genes (16.9%), Cohesin or CTCF genes (18.1%), and RAS pathway
      genes (15.7%)
    explanation: >-
      Quantifies the most recurrent cooperating SNV/Indel mutation classes in
      pediatric non-DS-AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NUP98-KDM5A cases carried mutations in RB1 almost without exception and
      demonstrated a decrease in expression of this gene
    explanation: >-
      Establishes RB1 loss as the near-universal cooperating lesion of
      NUP98-KDM5A AMKL.
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HOXr cases were found to be significantly enriched in activating MPL
      mutations
    explanation: >-
      Supports cooperating activating MPL mutations as a feature of the HOXr
      AMKL subgroup, supplying JAK-STAT signaling cooperative with the HOX
      expression program.
  downstream:
  - target: Megakaryoblast Accumulation and Marrow Failure
    description: >-
      Cooperating kinase, cohesin, and cell-cycle lesions amplify the
      proliferation and survival defects driven by the founding fusion
      oncogene, contributing to overt leukemic transformation.
- name: Megakaryoblast Accumulation and Marrow Failure
  description: >-
    Differentiation-blocked megakaryoblasts accumulate in the bone marrow,
    crowding out normal hematopoiesis. The accompanying release of
    megakaryocyte-derived cytokines (PDGF, TGF-beta) drives marrow stromal
    fibrosis, while cytopenias produce anemia, thrombocytopenia, and
    susceptibility to infection. In some patients leukemic cells circulate
    and infiltrate liver and spleen.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: megakaryocyte progenitor cell
    term:
      id: CL:0000553
      label: megakaryocyte progenitor cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid
      leukemia (AML) in which cells morphologically resemble abnormal
      megakaryoblasts.
    explanation: >-
      Defines the morphologic hallmark of AMKL, marrow accumulation of
      abnormal megakaryoblasts.
histopathology:
- name: Megakaryoblast Predominance
  finding_term:
    preferred_term: Megakaryoblasts Present
    term:
      id: NCIT:C155995
      label: Myeloblasts Present
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Bone marrow shows infiltration by abnormal blasts with megakaryocytic
    features (cytoplasmic blebs, basophilic cytoplasm) expressing CD41/CD61
    and often CD42b. Diagnosis requires a megakaryocytic immunophenotype on
    blasts comprising at least 20% of marrow cells (FAB M7 criteria).
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid
      leukemia (AML) in which cells morphologically resemble abnormal
      megakaryoblasts.
    explanation: Establishes the defining morphologic finding of AMKL.
- name: Marrow Reticulin Fibrosis
  finding_term:
    preferred_term: bone marrow fibrosis
    term:
      id: NCIT:C36212
      label: Bone Marrow Fibrosis
  frequency: FREQUENT
  description: >-
    Megakaryoblast-derived growth factors (PDGF, TGF-beta) stimulate stromal
    fibroblasts to deposit reticulin fibers, producing the dense marrow
    fibrosis that often makes aspirate dry-tap and necessitates trephine
    biopsy for diagnosis. Particularly prominent in infant t(1;22)
    RBM15-MKL1 AMKL.
phenotypes:
- category: Hematologic
  name: Acute Megakaryocytic Leukemia
  description: >-
    Defining clinical phenotype of AMKL, a megakaryocytic-lineage acute
    leukemia, classified as FAB M7 in the legacy AML scheme.
  phenotype_term:
    preferred_term: Acute megakaryocytic leukemia
    term:
      id: HP:0006733
      label: Acute megakaryocytic leukemia
  frequency: VERY_FREQUENT
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Low platelet count from megakaryocytic dysfunction and crowding of normal
    hematopoiesis; often the most prominent cytopenia at presentation.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  frequency: VERY_FREQUENT
- category: Hematologic
  name: Anemia
  description: >-
    Normocytic anemia from marrow replacement and ineffective erythropoiesis
    with associated fatigue and pallor.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  frequency: VERY_FREQUENT
- category: Hematologic
  name: Pancytopenia
  description: >-
    Combined anemia, thrombocytopenia, and neutropenia in many AMKL patients
    due to bone marrow infiltration and fibrosis.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  frequency: FREQUENT
- category: Hematologic
  name: Increased Megakaryocyte Count
  description: >-
    Marrow shows increased and dysmorphic megakaryocytes/megakaryoblasts as
    the principal proliferating population.
  phenotype_term:
    preferred_term: Increased megakaryocyte count
    term:
      id: HP:0005513
      label: Increased megakaryocyte count
  frequency: VERY_FREQUENT
- category: Hematologic
  name: Bone Marrow Fibrosis
  description: >-
    Reticulin and collagen deposition by activated stromal cells in response
    to megakaryoblast-derived growth factors, often producing a dry-tap
    aspirate. Especially prominent in t(1;22) RBM15-MKL1 infant AMKL.
  phenotype_term:
    preferred_term: Myelofibrosis
    term:
      id: HP:0011974
      label: Myelofibrosis
  frequency: FREQUENT
- category: Hematologic
  name: Bleeding Tendency
  description: >-
    Mucocutaneous bleeding, petechiae, and bruising secondary to severe
    thrombocytopenia and dysfunctional megakaryocytic platelet production.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  frequency: FREQUENT
- category: Hematologic
  name: Petechiae
  description: >-
    Pinpoint cutaneous hemorrhages from severe thrombocytopenia, often the
    presenting sign of AMKL in infants.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  frequency: FREQUENT
- category: Abdominal
  name: Hepatosplenomegaly
  description: >-
    Enlargement of liver and spleen from leukemic infiltration, characteristic
    of infant non-DS AMKL with t(1;22) RBM15-MKL1.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  frequency: OCCASIONAL
  subtype: Non-Down Infant AMKL
- category: Constitutional
  name: Fatigue
  description: >-
    Fatigue and reduced exercise tolerance from anemia and systemic
    leukemic effects.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  frequency: VERY_FREQUENT
- category: Infectious
  name: Recurrent Infections
  description: >-
    Increased susceptibility to bacterial and fungal infections from
    neutropenia and dysfunctional granulocytes.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  frequency: FREQUENT
biochemical:
- name: Megakaryocytic Immunophenotyping
  notes: >-
    Flow cytometry detects expression of platelet/megakaryocyte markers (CD41,
    CD42b, CD61) on at least a subset of leukemic blasts. Required to
    confirm megakaryocytic lineage and differentiate AMKL from other AMLs
    when blast morphology is ambiguous.
- name: Cytogenetic and FISH Analysis
  notes: >-
    Karyotyping and FISH detect t(1;22)(p13;q13) (RBM15-MKL1), the cryptic
    inv(16)(p13.3q24.3) (CBFA2T3-GLIS2, requires targeted RT-PCR/FISH because
    it is invisible on standard karyotype), NUP98 rearrangements, KMT2A
    rearrangements, and constitutional trisomy 21 in ML-DS.
- name: GATA1 Sequencing in DS
  notes: >-
    Sanger or targeted next-generation sequencing of GATA1 exon 2 detects
    truncating mutations in essentially all ML-DS and TAM cases. Used both
    diagnostically and for monitoring TAM clones in DS neonates.
- name: RT-PCR for Recurrent Fusions
  notes: >-
    RT-PCR with fusion-specific primers detects RBM15-MKL1, CBFA2T3-GLIS2,
    NUP98-KDM5A, and KMT2A partner fusions; also useful for minimal residual
    disease monitoring after therapy.
genetic:
- name: GATA1
  association: Somatic Initiating Mutation (ML-DS)
  subtype: ML-DS
  gene_term:
    preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  notes: >-
    Acquired N-terminal truncating mutations in GATA1 (most often in exon 2)
    introduce premature stop codons that abolish full-length GATA1 while
    preserving the GATA1s short isoform. Detected in essentially all TAM and
    ML-DS cases on a constitutional trisomy 21 background; not detected in
    non-DS AMKL.
  evidence:
  - reference: PMID:12172547
    reference_title: "Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukemic cells from every individual with DS-AMKL that we examined
      contain mutations in GATA1
    explanation: Establishes GATA1 mutation as the founding lesion of DS-AMKL.
- name: RBM15
  association: Somatic Oncogenic Fusion Partner
  subtype: Non-Down Infant AMKL
  gene_term:
    preferred_term: RBM15
    term:
      id: hgnc:14959
      label: RBM15
  notes: >-
    5' partner in the t(1;22)(p13;q13) RBM15-MKL1 (OTT-MAL) fusion that
    defines infant AMKL.
- name: MRTFA (MKL1)
  association: Somatic Oncogenic Fusion Partner
  subtype: Non-Down Infant AMKL
  gene_term:
    preferred_term: MRTFA
    term:
      id: hgnc:14334
      label: MRTFA
  notes: >-
    3' partner in the t(1;22)(p13;q13) RBM15-MKL1 (OTT-MAL) fusion. Originally
    described as MKL1/MAL; renamed MRTFA (myocardin-related transcription
    factor A).
- name: CBFA2T3
  association: Somatic Oncogenic Fusion Partner
  subtype: CBFA2T3-GLIS2 AMKL
  gene_term:
    preferred_term: CBFA2T3
    term:
      id: hgnc:1537
      label: CBFA2T3
  notes: >-
    5' partner in the cryptic inv(16)(p13.3q24.3) CBFA2T3-GLIS2 fusion of
    pediatric non-DS AMKL.
- name: GLIS2
  association: Somatic Oncogenic Fusion Partner
  subtype: CBFA2T3-GLIS2 AMKL
  gene_term:
    preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  notes: >-
    3' partner in the cryptic inv(16)(p13.3q24.3) CBFA2T3-GLIS2 fusion. GLIS2
    contributes a Hedgehog-pathway zinc finger transcription factor moiety
    that activates BMP signaling in the fusion.
  evidence:
  - reference: PMID:23153540
    reference_title: "An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic
      cells induced bone morphogenic protein (BMP) signaling and resulted in
      a marked increase in the self-renewal capacity of hematopoietic
      progenitors.
    explanation: >-
      Functional evidence that GLIS2 fused to CBFA2T3 induces BMP signaling
      and self-renewal.
- name: NUP98
  association: Somatic Oncogenic Fusion Partner
  subtype: NUP98-rearranged AMKL
  gene_term:
    preferred_term: NUP98
    term:
      id: hgnc:8068
      label: NUP98
  notes: >-
    Recurrent 5' partner in pediatric AMKL fusions, most commonly fused to
    KDM5A (also NSD1, BPTF). NUP98 fusions deregulate HOXA cluster expression
    and are associated with poor outcome.
- name: KDM5A
  association: Somatic Oncogenic Fusion Partner
  subtype: NUP98-rearranged AMKL
  gene_term:
    preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  notes: >-
    3' partner in the recurrent NUP98-KDM5A fusion of pediatric AMKL,
    contributing the JmjC histone H3K4 demethylase activity that mis-targets
    chromatin remodeling at HOX loci.
- name: KMT2A
  association: Cooperating Rearrangement
  gene_term:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  notes: >-
    KMT2A (MLL) gene rearrangements are detected in roughly 7-10% of pediatric
    non-DS AMKL and are mutually exclusive with the major fusion oncogenes.
  evidence:
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%;
      NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in
      6%. These aberrations were mutually exclusive.
    explanation: >-
      Quantifies recurrent aberration frequencies in 153 pediatric AMKL cases
      and notes mutual exclusivity.
treatments:
- name: Reduced-Intensity Cytarabine-Based Chemotherapy (ML-DS)
  description: >-
    Children with ML-DS have superior outcomes on reduced-intensity AML
    regimens that lower etoposide dose and omit maintenance therapy. The
    international ML-DS 2006 trial showed 5-year overall survival approaching
    90% with this approach, exploiting the heightened cytarabine sensitivity
    conferred by GATA1s and trisomy 21.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
  evidence:
  - reference: PMID:28400376
    reference_title: "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with myeloid leukemia associated with Down syndrome (ML-DS)
      have superior outcome compared with non-DS patients, but suffer from
      higher constitutional cytotoxic drug susceptibility.
    explanation: Establishes the rationale for therapy reduction in ML-DS.
- name: Intensive Pediatric AML Chemotherapy (Non-DS AMKL)
  description: >-
    Non-DS AMKL is treated with full-intensity multi-agent AML induction
    (cytarabine plus anthracycline) and consolidation. Outcomes remain
    inferior to ML-DS, particularly for CBFA2T3-GLIS2 and NUP98-KDM5A
    subtypes, motivating risk-adapted protocols.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
  evidence:
  - reference: PMID:28112737
    reference_title: "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of key genomic events in newly diagnosed non-DS-AMKL
      patients is important for risk stratification as these lesions have
      therapeutic implications.
    explanation: >-
      Supports the rationale for genomically risk-adapted intensive AML
      chemotherapy in non-DS pediatric AMKL.
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that these genetic aberrations may be used for risk group
      stratification of pediatric AMKL and for treatment tailoring.
    explanation: >-
      Supports tailoring of pediatric non-DS AMKL chemotherapy intensity
      based on genetic risk group.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic HSCT in first remission is considered for high-risk non-DS
    AMKL, particularly CBFA2T3-GLIS2-positive, NUP98-KDM5A-positive,
    KMT2A-rearranged, or monosomy 7 cases. Generally avoided in ML-DS, where
    chemotherapy alone produces excellent outcomes.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  evidence:
  - reference: PMID:27114462
    reference_title: "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7
      (NCK-7) independently predicted a poor outcome, compared with
      RBM15/MKL1-rearranged patients and those with AMKL not carrying these
      molecular lesions.
    explanation: >-
      Identifies the high-risk genetic subgroups for whom intensified therapy
      and HSCT consolidation are considered.
- name: TAM Surveillance and Pre-emptive Low-Dose Cytarabine
  description: >-
    DS neonates with transient abnormal myelopoiesis (TAM) are monitored for
    progression to ML-DS; symptomatic TAM with hyperleukocytosis,
    hepatosplenomegaly, or hepatic dysfunction may receive low-dose
    cytarabine to reduce mortality and progression risk.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
  evidence:
  - reference: PMID:14636651
    reference_title: "Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TMD is a common myeloid disorder that affects 10% of DS newborns and
      evolves to AMKL in nearly 30% patients.
    explanation: >-
      Justifies TAM surveillance given TAM frequency in DS newborns and
      substantial progression rate to AMKL.
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: hematologic malignancy
📚

References & Deep Research

Deep Research

1
Acute Megakaryoblastic Leukemia Deep Research Fallback ▸

Acute Megakaryoblastic Leukemia Deep Research Fallback

Provider Attempts

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

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

Evidence Scope Used For Curation

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

Curation Conclusions

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

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