Acute Myeloid Leukemia (AML)

Overview

Acute Myeloid Leukemia (AML) is a hematologic malignancy arising from myeloid progenitor cells, classified under the Leukemia main type in OncoTree (parent node MNM). Adult AML genomes are mutation-sparse (mean ~13 coding mutations per sample) yet nearly every tumor harbors at least one driver event across nine recognized functional gene categories: transcription-factor fusions, NPM1 mutations, tumor suppressors, DNA-methylation genes, activated signaling, chromatin modifiers, myeloid transcription factors, cohesin complex, and spliceosome genes.

Cohorts in the corpus

  • laml_tcga_pub — 200 adult de novo AML cases (50 WGS, 150 WES) from Washington University tissue banking (Nov 2001–Mar 2010); complemented by RNA-seq, microRNA-seq, 450k methylation, and SNP arrays. PMID:23634996

Recurrent alterations

  • TCGA WGS/WES of 200 adult de novo AML cases identified 23 significantly mutated genes (FDR <0.05 by MuSiC); near-universal driver coverage: transcription-factor fusions (18%), NPM1 (27%), tumor suppressors (16%), DNA-methylation genes (44%), activated signaling (59%), chromatin modifiers (30%), myeloid transcription factors (22%), cohesin complex (13%), spliceosome (14%); a novel NPM1 + DNMT3A + FLT3 co-occurring triplet defined a putative epigenetic AML subtype with distinct mRNA, miRNA, and CpG-sparse methylation signatures PMID:23634996
  • In a Sanger sequencing screen of 1,345 hematologic cancers for CALR exon 9 mutations, AML cases showed no CALR mutations, confirming that CALR indels are restricted to the MPN/MDS disease spectrum and are absent from acute myeloid leukemia. PMID:24325359
  • Papaemmanuil et al. 2016 sequenced 111 cancer genes in 1540 adults with AML (AMLSG trials), identifying 5234 driver mutations across 76 genes and 11 mutually exclusive genomic subgroups; three new categories (chromatin–spliceosome 18%, TP53–aneuploidy 13%, provisional IDH2 R172 1%) were defined, with the full genomic model achieving ~71% concordance for overall survival versus ~64% with ELN variables alone PMID:27276561.
  • Single-arm prospective trial (N=116, Washington University) of 10-day decitabine cycles: 100% blast clearance in TP53-mutant AML (21/21) vs 41% in TP53 wild-type (P<0.001); unfavorable-risk karyotype predicted response (67% vs 34%, P<0.001); remissions were short-lived and mutation clearance never complete; median OS 12.7 months (TP53-mutant) vs 15.4 months (TP53 wild-type, P=0.79) — substantially better than 4–6 months with conventional induction in TP53-mutant AML PMID:27959731.
  • PIPseq program (101 high-risk pediatric patients, Columbia University Medical Center) sequenced AML cases including KIT Asn655Lys, IDH1 R132C, JAK3 A573V, KMT2A-AFF1, NUP98-NSD1, PTPN11 G503V, CEBPA biallelic frameshift, CBFB-MYH11 fusion, and KMT2C E704X mutations/fusions; actionable alterations identified in 47% of hematologic cases PMID:28007021
  • Germline WES study of 372 pediatric cancer patients (Düsseldorf) included AML cases; hematologic neoplasms accounted for 57% of the cohort and LP/PVs in TP53, CHEK2, and ATM were among the most common drivers PMID:29489754
  • MC3 multi-center mutation calling project called somatic variants across 10,510 TCGA tumor/normal pairs including AML (LAML); AML recovered only 44% of legacy AWG calls because tumor-in-normal contamination in LAML skin ‘normals’ causes MC3’s conservative filtering to misclassify somatic calls as germline PMID:29596782
  • Pan-cancer aneuploidy analysis (10,522 TCGA tumors) found AML has one of the lowest aneuploidy scores (mean 1.6 arm-level alterations) across 33 cancer types, consistent with a predominantly mutation-driven rather than CNA-driven disease PMID:29622463

Subtypes

  • POLE ultramutated / FAB-based stratification. RNA-seq NMF consensus clustering identified 7 mRNA groups and 5 miRNA groups mapping onto FAB subtypes (M1, M3, M4, M5). PMID:23634996
  • Transcription-factor fusion-driven (PML-RARA, RUNX1-RUNX1T1, MYH11-CBFB, KMT2A fusions): favorable-risk; carry the fewest cooperating mutations (MLL-fused mean 2.09 vs. 5.24 overall, P=0.002). PMID:23634996
  • NPM1 + DNMT3A + FLT3 triple-mutant: putative novel intermediate-risk subtype with methylation loss in CpG-sparse regions and distinct miRNA signature (high miR-10a, low miR-424). PMID:23634996
  • TP53-mutant unfavorable-risk: mean 7.00 tier-1 mutations; mutually exclusive of FLT3 and NPM1; associated with complex cytogenetics. PMID:23634996

Therapeutic landscape

  • No drug treatments were administered or evaluated in the TCGA AML study; the dataset (laml_tcga_pub) was released as a public resource for risk-stratification and pathogenesis research. PMID:23634996
  • Authors argue that DNMT3A, IDH1/IDH2, and TET2 add prognostic value for intermediate-risk classification beyond the then-current markers (FLT3, NPM1, CEBPA, KIT). PMID:23634996

Sources

  • PMID:23634996 — TCGA Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013.

This page was processed by crosslinker on 2026-05-09. - PMID:24325359

This page was processed by crosslinker on 2026-05-09. - PMID:27276561 — Papaemmanuil et al. 2016, NEJM. Genomic classification and prognosis in AML; 1540 patients, 111-gene panel, 11 genomic subgroups.

This page was processed by entity-page-writer on 2026-05-15. - PMID:27959731

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This page was processed by wiki-cli on 2026-05-14. - PMID:29489754

This page was processed by wiki-cli on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15. - PMID:29622463

This page was processed by wiki-cli on 2026-05-15.