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Review
. 2017;2017:5473197.
doi: 10.1155/2017/5473197. Epub 2017 Feb 14.

Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis

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Free PMC article
Review

Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis

Sabah F Chaudry et al. Biomed Res Int. .
Free PMC article

Abstract

Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific "founder" mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP.

Conflict of interest statement

The authors declare that there is no conflict of interests.

Figures

Figure 1
Figure 1
DNA methylation by DNA methyltransferase enzymes. An illustration showing the positively charged histones binding the negatively charged DNA into compact chromatin to prevent gene transcription. The figure shows how other proteins can interact with histones to regulate transcription of genes. Modifications of histones tails such as acetylation and methylation change chromatin architecture, unwinding chromatin to allow access to the DNA sequence. Several other proteins, including chromatin remodellers, can also affect chromatin architecture. Regulators such as DNA methyltransferase enzymes are then able to access DNA to add methyl groups (CH3) to appropriate cytosine bases. The methyl group is added to the C5 position of the pyrimidine ring to produce 5-methylcytosine (5mC). Aberrant methylation as illustrated can inactivate tumor suppressor genes (through hypermethylation) and increase expression of oncogenes (through hypomethylation of promotor sites of these genes), both of which can contribute to leukaemogenesis.
Figure 2
Figure 2
Structure of DNMT3A splice isoforms, DNMT3B, and DNMT3L. Shown here is the structure of the DNMT3 enzymes. The ADD domain is related to the PHD- (plant homeodomain-) like regulator ATRX and has strong interactions with histones, which is thought to enhance its methylation activity. Meanwhile PWWP domain (Pro-Trp-Trp-Pro) is found to interact with DNA and heterochromatin to help carry out its function, among other proteins. The catalytic domain of the enzyme has motifs conserved across the isoforms. Motifs I are cofactor binding while motifs VIII and IX are for DNA binding and methylation activity at motifs IV, VI, and VIII. The main difference between the two splice isoforms of DNMT3A1 and DNMT3A2 is the extra DNA binding domain located at the amino terminal of DNMT3A1. Other DNMT enzymes are also able to interact with DNMT3A. One common mutation site shown here is R882 residue. This is a hotspot for mutations in haematological malignancy and preleukaemic conditions. Not depicted here are the splice isoforms for DNMT3B and the structure of DNMT1. Adapted from Yang et al. [2].
Figure 3
Figure 3
Some of the key classes of genes that are observed to contribute to the development of malignancy. All are potential targets for therapy in leukaemia. Adapted from Murati et al. [27].
Figure 4
Figure 4
Criteria for clonal haematopoiesis of indeterminate potential. Adapted from Steensma et al. [28]. Paroxysmal nocturnal haemoglobinuria (PNH), monoclonal gammopathy of unknown significance (MGUS), and monoclonal B-cell lymphocytosis (MBL).

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References

    1. Bird A. DNA methylation patterns and epigenetic memory. Genes and Development. 2002;16(1):6–21. doi: 10.1101/gad.947102. - DOI - PubMed
    1. Yang L., Rau R., Goodell M. A. DNMT3A in haematological malignancies. Nature Reviews Cancer. 2015;15(3):152–165. doi: 10.1038/nrc3895. - DOI - PMC - PubMed
    1. Holliday R., Grigg G. W. DNA methylation and mutation. Mutation Research. 1993;285(1):61–67. doi: 10.1016/0027-5107(93)90052-h. - DOI - PubMed
    1. Suzuki M. M., Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nature Reviews Genetics. 2008;9(6):465–476. doi: 10.1038/nrg2341. - DOI - PubMed
    1. Weber M., Hellmann I., Stadler M. B., et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics. 2007;39(4):457–466. doi: 10.1038/ng1990. - DOI - PubMed

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