Recurrent DNMT3A mutations in patients with myelodysplastic syndromes
Open accessAbstract
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
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DNMT3A is recurrently mutated in acute myeloid leukemia and myelodysplastic syndromes.
“DNMT3A is also recurrently mutated in blood diseases such as acute myeloid leukemia (AML; ref. 9) and myelodysplastic syndromes (MDS; ref. 10) where it functions as an initiating mutation (11).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [10]
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- Authors
- Walter, M. J., Ding, L., Shen, D., Shao, J., Grillot, M., McLellan, M., Fulton, R., Schmidt, H., Kalicki-Veizer, J., O'Laughlin, M., Kandoth, C., Baty, J., Westervelt, P., DiPersio, J. F., Mardis, E. R., Wilson, R. K., Ley, T. J., & Graubert, T. A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Graubert, T A
- ORCID
- Venue
- Leukemia
- Published
- 2011-03-18
- Volume
- 25
- Issue
- 7
- Pages
- 1153-1158
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC3202965
- OpenAlex
- W2010318973
- Cited by
- 527
- References
- 2
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 19 · 2023: 16 · 2022: 26 · 2021: 28 · 2020: 25 · 2019: 22 · 2018: 28 · 2017: 34 · 2016: 47 · 2015: 53 · 2014: 55 · 2013: 65 · 2012: 55
- FWCI
- 47.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (RC2HL102927, R01HL082973)
- National Human Genome Research Institute (U54HG003079)
- National Cancer Institute (P01CA101937)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- DNMT3A mutation, myelodysplastic syndrome, DNA methylation, DNA methyltransferases, secondary acute myeloid leukemia, prognostic factors, overall survival, disease progression, bone marrow
- MeSH terms
- DNA Methyltransferase 3A, Adult, Aged, Aged, 80 and over, Codon, DNA (Cytosine-5-)-Methyltransferases, DNA, Neoplasm, Exons, Female, Humans, Male, Middle Aged, Mutation, Myelodysplastic Syndromes, Prognosis, Leukemia, Myeloid, Acute, Sequence Analysis, DNA, Disease Progression, CpG Islands, DNA Methylation, Granulocyte Precursor Cells, Kaplan-Meier Estimate, Young Adult
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