Home / Deep Research / Acute Megakaryoblastic Leukemia

Acute Megakaryoblastic Leukemia

Acute Megakaryoblastic Leukemia Deep Research Fallback

⚠️ Fallback MONDO:0018872

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.