DNMT3A

Primary Author(s)*

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Synonyms

DNA Methyltransferase 3 Alpha, DNA (Cytosine-5-)-Methyltransferase 3A

Genomic Location

Cytoband: 2p23.3

Genomic Coordinates:

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chr2:25,455,845-25,565,459 (GRCh37/hg19)

chr2:25,227,855-25,342,590 (GRCh38/hg38)

Cancer Category/Type

Haematological malignancies e.g. • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • T-cell acute lymphoblastic leukaemia (T-ALL) • Peripheral T-cell lymphoma (PTCL) • Myeloproliferative neoplasm (MPN)

Gene Overview

The protein DNA (cytosine-5-)-methyltransferase 3A (DNMT3A) belongs to a family of highly conserved DNA methyltransferases that catalyse 5-methylcytosine methylation [1]. Regulatory domains of DNMT3A allow interactions with histone methyltransferases and histones to influence gene expression. Its properties (discussed later) are consistent with it being a tumor suppressor [1].

DNA methylation - DNA methylation refers to the addition of a methyl group to the C5 position of the pyrimidine ring of cytosines to form 5-methylcytosine [2,3]. It is mediated by a family of DNA methyltransferase enzymes, including DNMT1, DNMT3A and DNMT3B [2,3]. The related member DNMT3-like (DNMT3L) lacks a catalytic domain and functions as an accessory protein to DNMT3A during embryonic development and genomic imprinting [2,3]. DNMT1 primarily maintains pre-existing DNA methylation patterns, whereas DNMT3A and DNMT3B carry out de novo DNA methylation [1,4]. The methylcytosine dioxgenase protein (TET1, TET2 and TET3) convert 5-methylcytosine to 5-hydroxymethylcytosine [5]. Both hypo- and hypermethylation may be pathogenic in the context of cancer. Global hypomethylation may be associated with genomic instability. The amino-terminal catalytic region of DNMT3A is highly conserved [1,4]. See Figure 1 from [1].

DNMT3A-related disease - DNMT3A is important in embryonic and hematopoietic stem cell differentiation, and interacts with DNMT3B to regulate the function of stem cells [1]. Loss of murine DNMT3A causes hematopoietic stem cell expansion, clonal dominance, aberrant DNA methylation, an unrepressed stem cell programme and, ultimately, haematological [6,7]. When DNMT3A mutations occur in human hematopoietic stem cells they can act as a pre-leukemic lesion [1]. Mutant hematopoietic stem cell progenies are found in all differentiated lineages in some patients with AML; these mutant hematopoietic stem cells persist during disease remission [1]. DNMT3A mutations occur in diverse hematological malignancies with unique mutational profiles; the mutation allele and gene dosage, combined with secondary mutations, are presumed to dictate the type of hematological disease [1]. As mentioned earlier, DNMT3A mutations are likely to arise in the pre-leukemic HSC compartment, in which heterozygous mutations predispose the occurrence of myeloid disease and peripheral T-cell lymphoma, whereas homozygous mutations are likely to occur in T-cell disease [1]. Some mutations in DNMT3A Arg882 are associated with acquisition of co-mutations, e.g., internal tandem duplication in the gene encoding the receptor tyrosine kinase FLT3 and mutations in the gene encoding nucleophosmin NPM1 [8,9]. The acquisition of a secondary mutation in myeloid disease is associated with distinct myeloid neoplasms, including AML, MDS and myeloproliferative neoplasms (MPNs) [1]. See Figure 2 in [1].

DNMT3A in acute myeloid leukemia (AML) - DNMT3A mutations occur in approximately 25% of AML patients [8]. The most common mutation, DNMT3A Arg882His, has a dominant negative activity that reduces DNA methylation activity by approximately 80% in vitro [10,11]. Whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A Arg882 mutations has improved our understanding of DNMT3A in AML [10,11]. It must be noted that CpG island hypermethylation occurs as a consequence of rapid cellular proliferation and is therefore not a cancer-specific phenomenon [10,11]. DNMT3A Arg882His causes focal hypomethylation in non-leukemic human hematopoietic cells, suggesting that this hypomethylation precedes leukemia development and may represent an important initiating step for AML [10,11]. DNMT3A Arg882His-associated hypomethylation in pre-leukemic cells is maintained during AML progression, even during remission [10,11]. In AML, DNMT3A Arg882 causes focal methylation loss and attenuates hypermethylation [10,11]. The abnormal CpG island hypermethylation in AML is mediated by DNMT3A. Although virtually all AMLs with wild-type DNMT3A display CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A Arg882 mutations [10,11]. The absence of hypermethylation in AMLs with DNMT3A Arg882His suggests that DNMT3A is not required for leukemia progression [10,11]. In short, CpG island hypermethylation is a consequence of AML progression rather than a driver of transcriptional gene silencing during leukemogenesis [10,11]. See Figure in Highlights section of [10]. It is proposed that DNMT3A-dependent DNA methylation in AML cells acts as a 'brake' that prevents abnormal self-renewal; the abnormal CpG island hypermethylation in 'DNMT3A WT AMLs may be an adaptive response that is ultimately overcome during leukemia progression [11]. The absence of this 'braking' activity in AMLs with DNMT3A Arg882His may contribute directly to leukemia initiation [11]. The restoration of DNMT3A activity in AML cells with the DNMT3A Arg882His mutation is therefore a potential therapeutic goal [11].

Prognostic implications - A comprehensive review published in 2015 found that the prognostic impact of DNMT3A mutations across various haematological malignancies is inconclusive. Some studies have found that DNMT3A mutations are associated with a poor prognosis, while others have found that DNMT3A status is neutral in terms of prognosis [1,12,13,14]. Despite the lack of clarity regarding the impact of DNMT3A mutation on outcome, evidence in MDS, MPN and chronic myelomonocytic leukemia (CMML) suggests that the presence of a DNMT3A mutation may facilitate the transition from myeloproliferation and/or myelodysplasia to frank acute myeloid leukemia [1]. Some studies have reported significantly worse overall survival for patients with T-ALL who have DNMT3A mutations (it is not clear whether this is cause or correlation) [15]. However, the current available data suggest that the presence of DNMT3A mutation(s) is a negative prognostic marker independent of disease phenotype [1]. Thus, it appears reasonable to consider screening patients with T-ALL for mutations of DNMT3A to refine risk stratification [1]. DNMT3A mutations were associated with an unfavorable clinical outcome in the Southeast Asian AML patient cohort. The AML NPM1/FLT3/DNMT3A subtype was an independent predictor for poorer overall survival [16].

Therapeutic implications - Intensification of anthracycline treatment (e.g., idarubicin, daunorubicin) has been postulated to be more efficacious in AML in the context of DNMT3A variants [17]. Hypomethylating agents such as 5-azacytidine and decitabine, which may cause demethylation of aberrantly hypermethylated genes, are a potential therapy in the context of DNMT3A loss-of, or altered-function, variants [1,18].

Common Alteration Types

A mutational hotspot at Arg882, within the catalytic region, is reported in the context of AML, MDS, T-ALL/lymphoma. Much less common hotspots are Gly543 and Arg736, which are only reported in AML. Nonsense variants have been reported in the context of AML, MDS, and T-ALL/lymphoma, but are much more commonly seen in the context of T-ALL/lymphoma. Frameshift variants are more common in MDS and T-ALL/lymphoma than AML [1].

As mentioned previously, it is postulated that certain levels of functional loss, based on the presence of compound heterozygosity, the type and site of variants, the interaction of other proteins and residual wild-type expression levels contribute to the development of myeloid versus lymphoid malignancies. Biallelic variants are more common in the absence of an Arg882 variant. FLT3-ITD, NPM1 and IDH1 cooperating mutations are seen in the context of AML; SF3B1 and U2AF1 cooperating mutations in the context of MDS; IDH1 and IDH2 variants in isolation are associated with MPN; TET2, IDH2 and RHOA are associated with PTCL. See Figure 2 in [1]. Cooperating variants are not usually seen in the context of DNMT3A-mutated T-ALL, but DNMT3A biallelic variants are more commonly seen in T-ALL. Biallelic DNMT3A variants are rare in PTCL [1].

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
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Internal Pages

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External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

EXAMPLES

TP53 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

TP53 by COSMIC - sequence information, expression, catalogue of mutations

TP53 by CIViC - general knowledge and evidence-based variant specific information

TP53 by IARC - TP53 database with reference sequences and mutational landscape

TP53 by St. Jude ProteinPaint mutational landscape and matched expression data.

TP53 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

TP53 by Cancer Index - gene, pathway, publication information matched to cancer type

TP53 by OncoKB - mutational landscape, mutation effect, variant classification

TP53 by My Cancer Genome - brief gene overview

TP53 by UniProt - protein and molecular structure and function

TP53 by Pfam - gene and protein structure and function information

TP53 by GeneCards - general gene information and summaries

GeneReviews - information on Li Fraumeni Syndrome

References

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

EXAMPLE Journal Article

1. Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Notes

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