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DNMT3A in haematological malignancies

Key Points

  • 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.

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.

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Figure 1: The structure of DNA methyltransferase proteins and their binding partners.
Figure 2: Distribution of DNMT3A mutation frequency in myeloid and lymphoid leukaemia.
Figure 3: DNMT3A mutation allele and gene dosage, combined with secondary mutations, are likely to dictate the type of haematological disease.
Figure 4: Co-mutations with DNMT3A in acute myeloid leukaemia and other diseases.

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Acknowledgements

The authors thank C. Gillespie for critical comments on the manuscript. L.Y. is an M.D./Ph.D. McNair Scholar. This work was supported by US National Institutes of Health grants CA183252 and DK092883, the Sam Waxman Cancer Research Foundation and the Edward P. Evans Foundation.

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Frequency of DNMT3A mutations in hematologic disorders and their associated clinical phenotypes. (PDF 172 kb)

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Biochemical Impact of Mutations in Dnmt3a found in Cancer Patients (PDF 106 kb)

Glossary

Imprinting

A genetic phenomenon in which the expression status of each allele of a gene is dictated by the parent from which the allele was inherited. DNA methylation plays a part in the crucial parent-specific regulation of gene expression.

CpG

A dinucleotide pair on the same DNA strand consisting of cytosine (C) and guanine (G) nucleotides joined by a phosphodiester bond (p); CpGs are the predominant target of DNA methylation.

Repetitive elements

Stretches of DNA that are found in multiple copies (often many thousands) throughout the genome. Most represent types of transposable elements, the activity of which is partly repressed by DNA methylation.

Pericentromeric heterochromatin

Regions of compact genomic DNA and chromatin that are located near centromeres. Pericentromeric heterochromatin is associated with repressive chromatin marks and inactive gene transcription.

Teratoma formation assay

A stringent test of pluripotency in which embryonic (or other) stem cells are transplanted into a mouse and examined for their ability to differentiate into all three germ layers.

Variant-allele frequencies

(VAFs). The relative proportions of sequencing reads from variant alleles. Variants found at a VAF of 50% usually represent heterozygous mutations that are present in all cells within the sample (the founding clone). Lower VAFs suggest that the variant occurs in only a fraction of the cells (possible subclone).

Compound heterozygous

The presence of two different mutant alleles at a particular gene locus, on each chromosome of a pair.

Myelodysplastic syndrome

(MDS). A group of myeloid disorders characterized by clonal and ineffective haematopoiesis, dysplasia in one or more of the myeloid cell lines, cytopaenia(s) and increased risk of the development of acute myeloid leukaemia.

Myeloproliferative neoplasms

(MPNs). A heterogeneous group of clonal haematopoietic stem cell disorders characterized by the abnormal proliferation of one or more of the myeloid lineages.

Chronic myelomonocytic leukaemia

(CMML). A clonal haematological malignancy with features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. CMML is characterized by persistent monocytosis, dysplasia of one or more myeloid lineages, and < 20% blasts in the blood and bone marrow. By definition, CMML lacks the breakpoint cluster region (BCR)–ABL1 fusion gene and platelet-derived growth factor receptor-α (PDGFRA) or PDGFRB rearrangements.

Enhancers

Distal regulatory regions of the genome up to 1megabase upstream of transcription start sites defined by chromatin marks such as monomethylation of histone H3 lysine 4 (H3K4me1) and acetylation of H3K27 (H3K27ac). Enhancers are often bound by transcription factors.

Secondary acute myeloid leukaemia

(sAML). A documented myelodysplastic syndrome or myeloproliferative neoplasm that transforms into AML. This subset of AML is now included in the category 'AML with myelodysplasia-related changes'.

Spliceosome factor

A member of the large and complex molecular machinery known as the spliceosome, which functions to remove introns from a transcribed precursor mRNA.

De novo acute myeloid leukaemia

(De novo AML). Initial diagnosis of AML, not preceded by myelodysplastic syndrome or myeloproliferative neoplasm, and not associated with prior chemotherapy or radiation therapy.

Polycythaemia vera

A chronic myeloproliferative neoplasm characterized by aberrantly increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. Polycythaemia vera is molecularly characterized by activating mutations of the tyrosine kinase Janus kinase 2 (JAK2), which are present in nearly all patients with polycythaemia vera.

Essential thrombocythaemia

A chronic myeloproliferative neoplasm characterized by increased platelet count in the peripheral blood and megakaryocyte proliferation with large and mature morphology in the bone marrow. Essential thrombocytosis is characterized molecularly by activating mutations of the tyrosine kinase Janus kinase 2 (JAK2), which are present in 40–50% of patients with essential thrombocytosis.

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Yang, L., Rau, R. & Goodell, M. DNMT3A in haematological malignancies. Nat Rev Cancer 15, 152–165 (2015). https://doi.org/10.1038/nrc3895

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