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==Synonyms==
==Synonyms==
DNA Methyltransferase 3 Alpha, DNA (Cytosine-5-)-Methyltransferase 3A
==Genomic Location==
==Genomic Location==
'''Cytoband:''' Put your text here. EXAMPLE: 17p13.1
'''Cytoband:''' 2p23.3
'''Genomic Coordinates:'''
'''Genomic Coordinates:'''
Put your text here
Put your text here
chr2:25,455,845-25,565,459 (GRCh37/hg19)
chr2:25,227,855-25,342,590 (GRCh38/hg38)
==Cancer Category/Type==
==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==
==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 diseases
''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].
==Common Alteration Types==
==Common Alteration Types==