DNMT3A in Leukemia

Abstract

DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies. Here, we discuss the biology of DNMT3A and its role in controlling hematopoietic stem cell fate decisions. In addition, we review how mutant DNMT3A may contribute to leukemogenesis and the clinical relevance of DNMT3A mutations in hematologic cancers.

Figure 1.

DNMT3A genomic locus. The DNMT3A gene is composed of 23 exons distributed across ∼110,000 bp on chromosome 2. The two major isoforms, DNMT3A1 and DNMT3A2, are depicted along with the promoters and exons from which they are transcribed. The vertical dotted lines drawn on the different isoforms represent exon–exon junctions.

Figure 2.

DNMT3A controls hematopoietic stem cell fate. In mice, serial competitive transplantation of wild-type (WT) hematopoietic stem cells (HSCs) (CD45.2) eventually leads to less efficient engraftment. The contribution of engrafted HSCs to hematopoiesis is proportional to their level of engraftment in the bone marrow (top). In contrast, Dnmt3a-null HSCs do not exhaust and instead begin to outcompete CD45.1 WT cells, resulting in an expanded contribution to the HSC compartment. The contribution of these Dnmt3a-null HSCs to blood production is minimal, reflecting an imbalance between self-renewal and differentiation driven by loss of DNMT3A (bottom).

Figure 3.

DNMT3A mutations in acute myeloid leukemia (AML) and clonal hematopoiesis. The spectrum of DNMT3A mutations in AML (TCGA data) and clonal hematopoiesis (Jaiswal et al. 2014) are depicted on a figure of the long isoform. AML TCGA data include 57 DNMT3A mutations from 51 individuals (cohort of 200 patients), whereas clonal hematopoiesis data include 403 DNMT3A mutations from 398 individuals (cohort of 17,182 healthy patients). Each lollipop represents a nonsynonymous mutation, with the size of the lollipop correlating to the mutation count (within the respective groups) and the color indicating the type of mutation.