DNA methyltransferases in hematological malignancies

Abstract

DNA methyltransferases (DNMTs) are an evolutionarily conserved family of DNA methylases, transferring a methyl group onto the fifth carbon of a cytosine residue. The 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, whereas 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 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 functions 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. Finally, we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.

Keywords: DNA methylation; DNA methyltransferases; Leukemia; Lymphoma; Tumor suppressor.

Fig. 1.. Schematic structure of the mammalian DNMT family.

Shown are functional domains of human five DNMT members: DNMT1, DNMT3A, DNMT3B, DNMT3L and DNMT2. DNMT1, DNMT3A and DNMT3B have a catalytic methyltransferase domain (MTase). DNMT3L and DNMT2 harbor their truncated MTase domain and therefore do not have methyltransferase activity. In addition, DNMT1 has a charge-rich domain containing the proliferating cell nuclear antigen (PCNA) binding domain, an intrinsically disordered domain with a nuclear localization sequence (NLS), a replication foci target sequence (RFTS), a zinc finger domain (CXXC), and two bromo-adjacent homology domains (BAH 1/2). DNMT3A and DNMT3B have a PWWP domain and an ATRX-DNMTB-DNMT3L (ADD) that is also found in DNMT3L.

Fig. 2.. The role of DNMTs in normal B cell development and differentiation.

HSC: hematopoietic stem cells.

Fig. 3.. Model of instructive DNA methylation by DNMT1 and DNMT3A at promoter regions of tumor suppressor genes.

Whether DNMT3A interacts with these transcription factors/cofactors as a homo/heterotetramer or a monomer remains unknown. Brown diamonds: DNMT3A; green diamonds: DNMT3L.