DNMT3A mutations in myeloproliferative neoplasms

Abstract

Since the discovery of the gain-of-function mutation JAK2 V617F in 2005, an increasing number of mutations have been described in myeloproliferative neoplasms (MPN) and related myeloid malignancies.1, 2, 3, 4 For instance, use of array-based techniques such as comparative genomic hybridization and single-nucleotide polymorphism (SNP) analysis led to the identification of genes involved in epigenetic regulation such as tet-oncogene family member 2 (TET2), additional sex combs like 1 (ASXL1) and enhancer of zeste 2 (EZH2).5, 6, 7 Inactivating mutations in TET2, ASXL1 and EZH2 are considered to promote myeloid tumorigenesis because of epigenetic modulation of target genes. More recently, a whole-genome sequencing study in acute myeloid leukemia (AML) uncovered recurrent mutations in 22% of AML patients in another epigenetic regulator, the DNA methyltransferase 3A gene DNMT3A.8 In this study, DNMT3A mutations were associated with poor outcome and, thus, are of clinical relevance. However, exact mechanisms of action of DNMT3A mutations are still unclear because global methylation patterns and 5-methylcytosine content in AML genomes were not significantly altered. Nevertheless, mutations of TET2, ASXL1, EZH2 and DNMT3A occur in a significant number of patients with myeloid malignancies underlining the pathogenic relevance of epigenetic changes.