This study provides a comprehensive analysis of the genomic and epigenomic landscapes of adult de novo acute myeloid leukemia (AML). The researchers analyzed the genomes of 200 clinically annotated adult AML cases using whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. They found that AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations in genes. Of these, an average of 5 were in genes 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 one nonsynonymous mutation in one of nine categories of genes relevant to AML pathogenesis, including transcription-factor fusions, NPM1, tumor suppressor genes, DNA methylation-related genes, signaling genes, chromatin-modifying genes, myeloid transcription-factor genes, cohesin-complex genes, and spliceosome-complex genes. Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several genes and categories. The study identified at least one potential driver mutation in nearly all AML samples and revealed a complex interplay of genetic events contributing to AML pathogenesis in individual patients. The findings provide a foundation for further investigations into AML pathogenesis, classification, and risk stratification.This study provides a comprehensive analysis of the genomic and epigenomic landscapes of adult de novo acute myeloid leukemia (AML). The researchers analyzed the genomes of 200 clinically annotated adult AML cases using whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. They found that AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations in genes. Of these, an average of 5 were in genes 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 one nonsynonymous mutation in one of nine categories of genes relevant to AML pathogenesis, including transcription-factor fusions, NPM1, tumor suppressor genes, DNA methylation-related genes, signaling genes, chromatin-modifying genes, myeloid transcription-factor genes, cohesin-complex genes, and spliceosome-complex genes. Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several genes and categories. The study identified at least one potential driver mutation in nearly all AML samples and revealed a complex interplay of genetic events contributing to AML pathogenesis in individual patients. The findings provide a foundation for further investigations into AML pathogenesis, classification, and risk stratification.