DNMT3A Mutations in Acute Myeloid Leukemia
Open accessAbstract
BACKGROUND: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. METHODS: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. RESULTS: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. CONCLUSIONS: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.).
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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).”
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<i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i>
Zhang, C. R., Ostrander, E. L., Kukhar, O., Mallaney, C., Sun, J., Haussler, E., Celik, H., Koh, W. K., King, K. Y., Gontarz, P., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0132 · Cited by 23 · see citing works
Dietary nitrate, nitric oxide, and restenosis
Cooke, J. P., & Ghebremariam, Y. T. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57193 · Cited by 19 · see citing works
- Authors
- Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., Harris, C. C., Lichti, C. F., Townsend, R. R., Fulton, R. S., Dooling, D. J., Koboldt, D. C., Schmidt, H., Zhang, Q., Osborne, J. R., Lin, L., O'Laughlin, M., McMichael, J. F., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Magrini, V. J., Vickery, T. L., Hundal, J., Cook, L. L., Conyers, J. J., Swift, G. W., Reed, J. P., Alldredge, P. A., Wylie, T., Walker, J., Kalicki, J., Watson, M. A., Heath, S., Shannon, W. D., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M. H., Link, D. C., Graubert, T. A., DiPersio, J. F., Mardis, E. R., & Wilson, R. K.
- Affiliations
- Washington University in St. Louis (US)
- Alvin J. Siteman Cancer Center (US)
- ORCID
- Ley, Timothy J.
- Ding, Li
- Walter, Matthew J.
- McLellan, Michael D.
- Larson, David E.
- Kandoth, Cyriac
- Payton, Jacqueline E.
- Welch, John
- Lichti, Cheryl F.
- Townsend, R. Reid
- Fulton, Robert S.
- Koboldt, Daniel C.
- Lin, Ling
- McMichael, Joshua F.
- McGrath, Sean D.
- Magrini, Vincent J.
- Vickery, Tammi L.
- Hundal, Jasreet
- Cook, Lisa L.
- Wylie, Todd
- Walker, Jason
- Watson, Mark A.
- Heath, Sharon
- Tomasson, Michael H.
- Link, Daniel C.
- Graubert, Timothy A.
- DiPersio, John F.
- Mardis, Elaine R.
- Wilson, Richard K.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-12-16
- Volume
- 363
- Issue
- 25
- Pages
- 2424-2433
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3201818
- OpenAlex
- W2131072337
- Cited by
- 1,983
- References
- 1
- Citations by year
- 2026: 58 · 2025: 71 · 2024: 84 · 2023: 82 · 2022: 97 · 2021: 99 · 2020: 114 · 2019: 100 · 2018: 106 · 2017: 143 · 2016: 141 · 2015: 163 · 2014: 173 · 2013: 184 · 2012: 195
- FWCI
- 109.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (5p41rr000954-34)
- National Human Genome Research Institute (U54HG003079)
- National Cancer Institute (P01CA101937)
- National Center for Research Resources (P41-RR000954, UL1RR024992)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- DNMT3A mutation, acute myeloid leukemia, somatic mutations, DNA methyltransferases, FLT3 mutation, overall survival, prognostic factors, de novo AML
- MeSH terms
- DNA Methyltransferase 3A, Adult, DNA (Cytosine-5-)-Methyltransferases, DNA Mutational Analysis, Female, Humans, Karyotyping, Male, Middle Aged, Mutation, Prognosis, Leukemia, Myeloid, Acute, Gene Expression, Proportional Hazards Models, Survival Analysis, Frameshift Mutation, DNA Methylation, Nucleic Acid Amplification Techniques
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