BACKGROUND—Many mutations that contribute to the pathogenesis of acute myeloid
leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic
phenotypes are not yet clear.
METHODS—We analyzed the genomes of 200 clinically annotated adult cases of de novo AML,
using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along
with RNA and microRNA sequencing and DNA-methylation analysis.
RESULTS—AML genomes have fewer mutations than most other adult cancers, with an average
of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently
mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in
two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine
categories of genes that are almost certainly relevant for pathogenesis, including transcriptionfactor
fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumorsuppressor
genes (16%), DNA-methylation–related genes (44%), signaling genes (59%),
chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex
genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual
exclusivity suggested strong biologic relationships among several of the genes and categories.
CONCLUSIONS—We identified at least one potential driver mutation in nearly all AML
samples and found that a complex interplay of genetic events contributes to AML pathogenesis in
individual patients. The databases from this study are widely available to serve as a foundation for
further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the
National Institutes of Health.