Changes

==Primary Author(s)*==

==Primary Author(s)*==

Kay Weng Choy (MBBS, BMedSci, FAACB)

Kay Weng Choy, MBBS, Monash Medical Centre

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'''Cytoband:''' 2p23.3

'''Cytoband:''' 2p23.3

'''Genomic Coordinates:'''  

'''Genomic Coordinates:'''

 

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

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

Haematological malignancies e.g.

Haematological malignancies e.g.

• Acute myeloid leukemia (AML)

*Acute myeloid leukemia (AML)

 

*Myelodysplastic syndrome (MDS)

• Myelodysplastic syndrome (MDS)

*T-cell acute lymphoblastic leukaemia (T-ALL)

 

*Peripheral T-cell lymphoma (PTCL)

• T-cell acute lymphoblastic leukaemia (T-ALL)

*Myeloproliferative neoplasm (MPN)

 

• 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].   

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].

* 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'' 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'' 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].

* 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].

* 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==

==Common Alteration Types==

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].

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].

==Internal Pages==

==Internal Pages==

18. Toyota M, et al., (2001). Methylation profiling in acute myeloid leukemia. Blood 97(9):2823-2829, PMID 11313277.

18. Toyota M, et al., (2001). Methylation profiling in acute myeloid leukemia. Blood 97(9):2823-2829, PMID 11313277.

== Notes ==

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.