DNA methyltransferases in hematological malignancies

Abstract DNA methyltransferases (DNMTs) are an evolutionarily conserved family of DNA methylases, transferring a methyl group onto the 5-position of cytosine. Mammalian DNMT family includes three major members that have functional methylation activities, termed DNMT1, DNMT3A and DNMT3B. DNMT3A and DNMT3B are responsible for methylation establishment while DNMT1 maintains methylation during DNA replication. Accumulating evidence demonstrates that regulation of DNA methylation by DNMTs is critical for normal hematopoiesis. Aberrant DNA methylation due to DNMT dysregulation and mutations, however, is known as an important molecular event of hematological malignancies, such as DNMT3A mutations in acute myeloid leukemia. In this review, we first describe the basic methylation mechanisms of DNMTs and their function in lymphocyte maturation and differentiation. We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets. We also discuss DNMT mutations and pathogenic roles in human leukemia and lymphoma. We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes. Lastly, we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.