Genomic structure, evolution and molecular classification of acute myeloid leukemia

Description: Description from GEO: "Background: Acute myeloid leukemia (AML) is driven by somatic mutations and genomic rearrangements affecting >20 genes. Many of these are recent discoveries and how this molecular heterogeneity dictates AML pathophysiology and clinical outcome remains unclear. Methods: We sequenced 111 leukemia genes for driver mutations in 1540 AML patients with cytogenetic and clinical data. We modeled AML’s genomic structure, defining genetic interactions, patterns of temporal evolution and clinical correlations. Results: We identified 5,236 driver mutations involving 77 loci, including hotspot mutations in MYC. We found ≥1 driver mutation in 96% patients, and ≥2 in 85%. Gene mutations implicated in age related clonal hematopoiesis (DNMT3A, ASXL1, TET2) were the earliest in AML evolution, followed by highly specific and ordered patterns of co-mutation in chromatin, transcription and splicing regulators, NPM1 and signaling genes. The patterns of co-mutation compartmentalize AML into 12 discrete molecular classes, each presenting with distinct clinical manifestation. Amongst these, mutations in chromatin and spliceosome genes demarcate a molecularly heterogeneous subgroup enriched for older AML patients currently classified as intermediate risk and results in adverse prognosis. Two- and three-way genetic interactions often implicating rare genes/mutation-hotspots, markedly redefined clinical response and long-term curability, with the NPM1:DNMT3A:FLT3ITD genotype (6% patients) identifying poor prognosis disease, whereas within the same class NPM1:DNMT3A:NRASG12/13 (3%) associated with favorable outlooks. Conclusions: 79% of AML is molecularly classified in 12 genomic subgroups. These represent distinct molecular phylogenies, implicating complex genotypes. Delineation of higher-order genomic relationships, guide the development of personally tailored classification, prognostication and clinical protocols. Similar studies across cancer types are warranted."

Design Description from GEO: "Gene expression was profiled in 46 AML samples [n=18 AML cases with MYC mutations and n=28 AML cases with MYC wild-type]."
Local Expert: Bullinger, Lars

Papaemmanuil, Elli

Subject of Study

Homo sapiens

Subject(s)

Leukemia, Myeloid

Leukemia, Myeloid, Acute

OncoTree Cancer Type(s)

Acute Myeloid Leukemia

Access via GEO
CEL expression profiling by array
Accession #: GSE70124

Access via BioProject
Additional information about overall initiative
Accession #: PRJNA287683
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications: Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. New England Journal of Medicine. 2016; 374(23):2209-2221.
Data Type: Genomic
Equipment Used: Affymetrix Human Genome U133 Plus 2.0 Array
Software Used: GEO2R
Use GEO2R to compare two or more groups of Samples in order to identify genes that are differentially expressed across experimental conditions. Results are presented as a table of genes ordered by significance.
Study Type: Observational
Dataset Format(s): TAR, CEL
Dataset Size: 224.2 MB (TAR of CEL)

Data Catalog Record Updated: 2021-10-19