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''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-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].

''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].