DNMT3A in haematological malignancies

Abstract

DNA methyltransferase 3A (DNMT3A) belongs to a family of highly conserved DNA methyltransferases that catalyse 5-methylcytosine methylation. Regulatory domains of DNMT3A allow interactions with histone methyltransferases and histones to influence gene expression. DNMT3A is important in embryonic and haematopoietic stem cell (HSC) differentiation, and interacts with DNMT3B to regulate the function of stem cells. Loss of murine Dnmt3a causes unprecedented HSC expansion, clonal dominance, aberrant DNA methylation, an unrepressed stem cell programme and, eventually, haematological malignancies. DNMT3A mutations occur in human HSCs, in which they can act as a pre-leukaemic lesion. Mutant HSC progeny are found in all differentiated lineages in some patients with acute myeloid leukaemia (AML), and mutant HSCs persist during disease remission. DNMT3A mutations occur in diverse haematological malignancies with unique mutational profiles. The R882 hotspot mutation occurs most frequently in AML and has been shown to act as a dominant-negative inhibitor of wild-type DNMT3A enzymatic activity. DNMT3A mutations non-randomly co-occur with a number of other mutations but can also be essentially mutually exclusive of others. This pattern suggests important biological relationships among these genes. The prognostic impact of DNMT3A mutations across various haematological malignancies is inconclusive. A number of studies have found that mutations of DNMT3A confer a poor prognosis, but others have found that DNMT3A status is prognostically neutral. Haematopoiesis becomes clonal in a significant portion of ageing individuals and is associated with increased incidence of haematological malignancy and all-cause mortality; mutations in DNMT3A are highly associated with this phenomenon. Given the strong association between DNMT3A mutations and many types of haematological malignancy and the relatively poor understanding of its mechanistic function, DNMT3A represents an important new target for research and novel therapeutic approaches.