Difference between revisions of "DNMT3A"

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==Primary Author(s)*==
 
==Primary Author(s)*==
  
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Kay Weng Choy, MBBS, Monash Medical Centre
  
 
__TOC__
 
__TOC__
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==Synonyms==
 
==Synonyms==
  
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DNA Methyltransferase 3 Alpha, DNA (Cytosine-5-)-Methyltransferase 3A
 
 
EXAMPLE: Tumor protein p53, ''LFS1, p53, BCC7, TRP53''
 
  
 
==Genomic Location==
 
==Genomic Location==
  
'''Cytoband:''' Put your text here. EXAMPLE: 17p13.1
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'''Cytoband:''' 2p23.3
  
'''Genomic Coordinates:'''  
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'''Genomic Coordinates:'''
  
Put your text here
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chr2:25,455,845-25,565,459 (GRCh37/hg19)
  
EXAMPLE: chr17:7,571,720-7,590,868 [hg19]
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chr2:25,227,855-25,342,590 (GRCh38/hg38)
  
EXAMPLE: chr17:7,668,402-7,687,538 [hg38]
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==Cancer Category/Type==
  
==Cancer Category/Type==
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Haematological malignancies e.g.
  
Put your text here
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*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==
  
Put your text here.
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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==
 
==Common Alteration Types==
  
Put your text here and/or fill in the table with an X where applicable
+
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].
  
{| class="wikitable sortable"
+
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
 
|-
 
| EXAMPLE: X ||EXAMPLE: X  || EXAMPLE: X  || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X
 
|}
 
  
 
==Internal Pages==
 
==Internal Pages==
  
Put your text here
+
Not applicable.
 
EXAMPLE [[Germline Cancer Predisposition Genes]]
 
  
 
==External Links==
 
==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.
+
'''[http://atlasgeneticsoncology.org/Genes/DNMT3AID40349ch2p23.html ''DNMT3A'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
 +
 
 +
'''[https://cancer.sanger.ac.uk/cosmic/search?q=DNMT3A ''DNMT3A'' by COSMIC]''' - sequence information, expression, catalogue of mutations
 +
 
 +
'''[https://civicdb.org/events/genes/18/summary/variants/189/summary ''DNMT3A'' by CIViC]''' - general knowledge and evidence-based variant specific information
 +
 
 +
'''[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=DNMT3A ''DNMT3A'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
 +
 
 +
'''[http://www.cancer-genetics.org/DNMT3A.htm ''DNMT3A'' by Cancer Genetics Web]''' - gene, pathway, and publication information matched to cancer type
 +
 
 +
'''[http://oncokb.org/#/gene/DNMT3A ''DNMT3A'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
 +
 
 +
'''[https://www.mycancergenome.org/content/gene/dnmt3a/ ''DNMT3A'' by My Cancer Genome]''' - brief gene overview
 +
 
 +
'''[https://www.uniprot.org/uniprot/Q9Y6K1 ''DNMT3A'' by UniProt]''' - protein and molecular structure and function
 +
 
 +
'''[https://pfam.xfam.org/search/keyword?query=DNMT3A ''DNMT3A'' by Pfam]''' - gene and protein structure and function information
  
EXAMPLES
+
'''[https://www.genecards.org/cgi-bin/carddisp.pl?gene=DNMT3A&keywords=DNMT3A ''DNMT3A'' by GeneCards]''' - general gene information and summaries
  
'''[http://atlasgeneticsoncology.org/Genes/P53ID88.html ''TP53'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
+
==References==
  
'''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=TP53 ''TP53'' by COSMIC]''' - sequence information, expression, catalogue of mutations
+
1. Yang L, et al., (2015). DNMT3A in haematological malignancies. Nat Rev Cancer 15(3):152-165, PMID 25693834.
  
'''[https://civicdb.org/events/genes/45/summary/variants/1300/summary ''TP53'' by CIViC]''' - general knowledge and evidence-based variant specific information
+
2. Wienholz BL, et al., (2010). DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. PLoS Genet 6(9):e1001106, PMID 20838592.
 +
 +
3. Kaneda M, et al., (2004). Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429(6994):900-903, PMID 15215868.
  
'''[http://p53.iarc.fr/ ''TP53'' by IARC]''' - ''TP53'' database with reference sequences and mutational landscape
+
4. Xu F, et al., (2010). Molecular and enzymatic profiles of mammalian DNA methyltransferases: structures and targets for drugs. Curr Med Chem 17(33):4052-4071, PMID 20939822.  
  
'''[https://pecan.stjude.cloud/proteinpaint/tp53 ''TP53'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data.  
+
5. Tahiliani M, et al., (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930-935, PMID 19372391.
  
'''[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=tp53 ''TP53'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
+
6. Challen GA, et al., (2011). Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44(1):23-31, PMID 22138693.
 +
 +
7. Mayle A, et al., (2015). Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125(4):629-638, PMID 25416277.
  
'''[http://www.cancerindex.org/geneweb/TP53.htm ''TP53'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type
+
8. Ley TJ, et al., (2010). DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363(25):2424-2433, PMID 21067377. 
  
'''[http://oncokb.org/#/gene/TP53 ''TP53'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
+
9. Patel JP, et al., (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Eng J Med 366(12):1079-1089, PMID 22417203.
  
'''[https://www.mycancergenome.org/content/gene/tp53/ ''TP53'' by My Cancer Genome]''' - brief gene overview
+
10. Spencer DH, et al., (2017). CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell 168(5):801-816, PMID 28215704.
  
'''[http://www.uniprot.org/uniprot/P04637 ''TP53'' by UniProt]''' - protein and molecular structure and function
+
11. Spencer D, et al., (2016). DNMT3A-dependent DNA methylation may act as a tumor suppressor – not a tumor promoter – during AML progression (Abstract). Blood 128(22):1050.
  
'''[https://pfam.xfam.org/family/p53 ''TP53'' by Pfam]''' - gene and protein structure and function information
+
12. Walter MJ, et al., (2011). Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25(7):1153-1158, PMID 21415852.
  
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=tp53 ''TP53'' by GeneCards]''' - general gene information and summaries
+
13. Bejar R, et al., (2012). Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 30(27):3376-3382, PMID 22869879.
  
'''[https://www.ncbi.nlm.nih.gov/books/NBK1311/ GeneReviews]''' - information on Li Fraumeni Syndrome
+
14. Roller A, et al., (2013). Landmark analysis of DNMT3A mutations in hematological malignancies. Leukemia 27(7):1573-1578, PMID 23519389.
  
==References==
+
15. Grossmann V, et al., (2013). The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 52(4):410-422, PMID 23341344.
 +
 +
16. Tan M, et al., (2017). Clinical implications of DNMT3A mutations in a Southeast Asian cohort leukaemia patients. J Clin Pathol 70(8):669-676, PMID 28100593.
  
=== EXAMPLE Book ===
+
17. LaRochelle O, et al., (2011). Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience. Oncotarget 2(11):850-861, PMID 22081665.  
#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 ===
+
18. Toyota M, et al., (2001). Methylation profiling in acute myeloid leukemia. Blood 97(9):2823-2829, PMID 11313277.
#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 ==
+
==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.
 +
 +
[[Category:Cancer Genes D]]

Latest revision as of 18:10, 5 January 2019

Primary Author(s)*

Kay Weng Choy, MBBS, Monash Medical Centre

Synonyms

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

Genomic Location

Cytoband: 2p23.3

Genomic Coordinates:

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].

Internal Pages

Not applicable.

External Links

DNMT3A by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

DNMT3A by COSMIC - sequence information, expression, catalogue of mutations

DNMT3A by CIViC - general knowledge and evidence-based variant specific information

DNMT3A by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

DNMT3A by Cancer Genetics Web - gene, pathway, and publication information matched to cancer type

DNMT3A by OncoKB - mutational landscape, mutation effect, variant classification

DNMT3A by My Cancer Genome - brief gene overview

DNMT3A by UniProt - protein and molecular structure and function

DNMT3A by Pfam - gene and protein structure and function information

DNMT3A by GeneCards - general gene information and summaries

References

1. Yang L, et al., (2015). DNMT3A in haematological malignancies. Nat Rev Cancer 15(3):152-165, PMID 25693834.

2. Wienholz BL, et al., (2010). DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. PLoS Genet 6(9):e1001106, PMID 20838592.

3. Kaneda M, et al., (2004). Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429(6994):900-903, PMID 15215868.

4. Xu F, et al., (2010). Molecular and enzymatic profiles of mammalian DNA methyltransferases: structures and targets for drugs. Curr Med Chem 17(33):4052-4071, PMID 20939822.

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Notes

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