Molecular genetics of AML

In the past decade, a series of technological advances have revolutionized our ability to interrogate cancer genomes, culminating in whole-genome sequencing, which provides genome-wide coverage at a single base-pair resolution. To date, the tumor genome has been sequenced in nearly 40 cases of acute myeloid leukemia (AML). On average, each AML genome contains approximately 400 mutations, including 6–26 coding mutations. The majority of these mutations are ‘background’ mutations that were acquired during normal aging of hematopoietic stem cells. Though comprehensively identifying ‘driver’ mutations remains a challenge, a number of novel driver mutations in AML have been identified through whole-genome sequencing. The digital nature of next-generation sequencing has revealed clonal heterogeneity in the majority of AML at diagnosis. Importantly, in some cases, a minor subclone contributed to relapse, suggesting the strategies to assess clonal heterogeneity are needed to optimize therapy. As sequencing technologies improve and costs decrease, it is likely that whole-genome sequencing of cancer cells will become commonplace in the diagnostic work-up of patients with AML and other cancers.