The study analyzed 200 adult de novo acute myeloid leukemia (AML) cases using whole-genome and exome sequencing, along with RNA, microRNA, and DNA methylation data. It identified 2315 somatic single-nucleotide variants (SNVs) and 270 small insertions/deletions (indels) in coding regions, with an average of 13 mutations per sample. Most mutations were in genes related to DNA methylation, signaling, and chromatin modification. A total of 23 genes were significantly mutated, and 237 genes were mutated in two or more samples. Nearly all samples had at least one nonsynonymous mutation in genes relevant to AML pathogenesis. Mutations in transcription-factor fusions, DNA-methylation-related genes, and signaling genes were common. The study found that mutations in FLT3, NPM1, CEBPA, and IDH1/2 were frequently associated with AML. The results suggest that a complex interplay of genetic events contributes to AML pathogenesis. The study also identified gene fusions, such as PML-RARA, RUNX1-RUNX1T1, and MLL-MLLT3/AF9, which are associated with favorable outcomes. DNA methylation analysis revealed significant differences in methylation patterns among AML subtypes. The study highlights the importance of understanding the genetic and epigenetic changes in AML for better classification and treatment strategies. The data are available for further research. The study was funded by the National Institutes of Health.The study analyzed 200 adult de novo acute myeloid leukemia (AML) cases using whole-genome and exome sequencing, along with RNA, microRNA, and DNA methylation data. It identified 2315 somatic single-nucleotide variants (SNVs) and 270 small insertions/deletions (indels) in coding regions, with an average of 13 mutations per sample. Most mutations were in genes related to DNA methylation, signaling, and chromatin modification. A total of 23 genes were significantly mutated, and 237 genes were mutated in two or more samples. Nearly all samples had at least one nonsynonymous mutation in genes relevant to AML pathogenesis. Mutations in transcription-factor fusions, DNA-methylation-related genes, and signaling genes were common. The study found that mutations in FLT3, NPM1, CEBPA, and IDH1/2 were frequently associated with AML. The results suggest that a complex interplay of genetic events contributes to AML pathogenesis. The study also identified gene fusions, such as PML-RARA, RUNX1-RUNX1T1, and MLL-MLLT3/AF9, which are associated with favorable outcomes. DNA methylation analysis revealed significant differences in methylation patterns among AML subtypes. The study highlights the importance of understanding the genetic and epigenetic changes in AML for better classification and treatment strategies. The data are available for further research. The study was funded by the National Institutes of Health.