DNMT3A in haematological malignancies

Abstract

DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.

Dnmt3a restrains mast cell inflammatory responses

“…7B). Consistent with the published observation that dif- (4,24,25), we found that an intergenic region in the proximity of the Iqgap2 locus was substantially hypomethylated in KO cells (Fig. 7B).…”

“…S1D). Second, the differentially methylated regions identified in Dnmt3a-null cells showed substantial hyper-as well as hypomethylation at a variety of genomic regions, with very little correlation between changes in methylation and differential gene expression in the absence of Dnmt3a in both mouse and human cells (4,24,25). These observations suggest the existence of both direct and indirect effects due to the loss of Dnmt3a, and potentially also the existence of DNMT3A activities that are independent of its DNA catalytic activity (26), similar to what has been described for the catalytically inactive DNMT3L (27), some of the DNMT3B isoforms (28), and even for the TET family of DNA-modifying enzymes (29,30).…”

“…Such a process is carried out by three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), and has a critical role in the control of gene expression (1,2). In general, high levels of DNA methylation are associated with transcriptional silencing (3), especially when present at promoter regions and at repetitive elements (4), although the function of DNA methylation at other genomic features and its correlation with gene expression are more uncertain (3)(4)(5). Whereas DNMT1 is thought to be primarily responsible for copying the preexisting methylation to the newly synthesized DNA strand during replication, DNMT3A and DNMT3B display significant affinity also for unmethylated DNA, and are therefore considered de novo methyltransferases (6,7).…”

“…More specific to the hematopoietic compartment, loss of Dnmt1 in hematopoietic stem cells (HSCs) led to defects in self-renewal, niche retention, as well as altered cell differentiation, especially toward the myeloid lineage (10), whereas loss of both Dnmt3a and Dnmt3b impaired HSC self-renewal capabilities (11). Importantly, aberrant DNA methylation is a hallmark of many diseases, including autoimmune diseases and especially various types of cancer (4,5). Mutations in DNMT3A have been found in a variety of hematological malignancies (4,12,13), including systemic mastocytosis, a clonal proliferative disorder of mast cells (14), pointing toward a role for DNMT3A in modulating mast cell biology.…”

“…Importantly, aberrant DNA methylation is a hallmark of many diseases, including autoimmune diseases and especially various types of cancer (4,5). Mutations in DNMT3A have been found in a variety of hematological malignancies (4,12,13), including systemic mastocytosis, a clonal proliferative disorder of mast cells (14), pointing toward a role for DNMT3A in modulating mast cell biology. Further correlating DNA methylation with the biology of mast cells (which are key effector cells in asthmatic and allergic responses), a recent survey compared atopic and asthmatic patients with healthy controls and identified 81 differentially methylated regions (15); the hypomethylated regions included genes such as IL13, which is not only crucial in asthma pathogenesis but is also expressed at high levels by mast cells (16).…”