Mutations in epigenetic modi fi ers in the pathogenesis and therapy of acute myeloid leukemia

Acute myeloid leukemia (AML) is a clonal disorder of hematopoiesis characterized by the accumulation of immature myeloid cells accompanied by impaired normal hematopoiesis. Given the need to improve outcome in AML, multiple studies aimed at genetic characterization of AML have been performed in the hopes of furthering our understanding of AML pathogenesis and identifying new therapeutic approaches. To this end, a number of targeted sequencing, exome sequencing, and whole-genome sequencing studies have been performed in AML patients in the last 5 to 10 years. From these studies, a number of recurrently mutated genes have been identified and, interestingly, many of the newly identified recurrently mutated genes encode proteins that normally function in the epigenetic regulation of transcription. Although the definition of the term epigenetics has been a matter of debate, in this review, we refer to epigenetics as any process that directly affects modifications of DNA cytosine residues or posttranslational modifications of histones. This includes frequent mutations in the genes DNMT3A (DNA nucleotide methyltransferase 3A), TET2 (teneleven translocation 2), IDH1/2 (isocitrate dehydrogenase 1/2), and ASXL1 (the addition of sex combs like 1) in AML patients (mutations and translocations in MLL1 will be discussed in another accompanying review in this series) (Table 1). Although prior DNA methylation profiling studies in AML have identified the presence of a profoundly abnormal epigenome in this disease, the identification of mutations in epigenetic regulatory genes now provides a link between the altered epigenome in AML and somatic genetic alterations in this disorder. From the studies of these genes in different AML cohorts, several common themes have already emerged. First, mutations in recently identified epigenetic modifiers are enriched in adults with AML (ages 16 years old and above) compared with pediatric AML patients. Indeed, the frequency of mutations in epigenetic modifiers correlates with increasing age of AML patients. Second, from studies evaluating the impact of these mutations in the hematopoietic system of genetically engineered mice, it appears that mutations in several of these genes affect hematopoietic self-renewal and/or differentiation without being sufficient for leukemogenesis on their own. Consistent with this notion, somatic mutations in TET2 andDNMT3A have been described in the hematopoietic system of elderly individuals before the occurrence of clinically apparent myeloid malignancy. Lastly, a number of studies integrating mutational analysis with clinical outcome in the setting of prospective clinical trials in AML have identified mutations as markers of prognostic risk stratification in AML. In addition to the prognostic importance of mutations in epigenetic modifiers, there may be important therapeutic implications of specific mutations in epigenetic pathways. In this review, we describe the clinical, biological, and therapeutic implications of mutations in genes encoding epigenetic modifiers which have been identified to be mutated in . 5% of patients with AML.