Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Open accessAbstract
Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis.
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Several 2-oxoglutarate-dependent chromatin enzymes, including UTX, JARID1C, and TET2, are targets of inactivating mutations in cancer, making them candidates for pathogenic inhibition by succinate, fumarate, and R-2HG.
“A number of 2-oxoglutarate-dependent enzymes that act on chromatin are themselves targets of inactivating mutations in cancer, including the UTX H3K27 demethylase (also called KDM6A), JARID1C H3K4 demethylase (KDM5C), and TET2, making them attractive candidates for pathogenically relevant inhibition by succinate, fumarate, and R-2HG (Abdel-Wahab et al., 2009; Dalgliesh et al., 2010; Tefferi et al”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Abdel-Wahab et al., 2009
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“…the prognostic relevance of these mutations in MDS, CMML and AML remains unclear, and may be disease-specific, as currently existing data are inconsistent (Abdel-Wahab et al., 2009; Kosmider et al., 2009a, b; Liu et al., 2013; Metzeler et al., 2011b; Pollyea et al., 2011; Wang et al., 2013a).”
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- Authors
- Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., Huberman, K., Thomas, S., Dolgalev, I., Heguy, A., Paietta, E., Le Beau, M. M., Beran, M., Tallman, M. S., Ebert, B. L., Kantarjian, H. M., Stone, R. M., Gilliland, D. G., Crispino, J. D., & Levine, R. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Brigham and Women's Hospital (US)
- Department of Leukemia, M. D. Anderson Cancer Center, Houston, TX;
- Human Oncology and Pathogenesis Program, and
- Dana-Farber Cancer Institute (US)
- Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL;
- Northwestern University (US)
- Montefiore Medical Center (US)
- Section of Hematology/Oncology, University of Chicago, IL;
- The University of Texas MD Anderson Cancer Center (US)
- Broad Institute (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-07-02
- Volume
- 114
- Issue
- 1
- Pages
- 144-147
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2710942
- OpenAlex
- W2073872690
- Cited by
- 727
- References
- 24
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 20 · 2023: 23 · 2022: 36 · 2021: 41 · 2020: 37 · 2019: 32 · 2018: 37 · 2017: 52 · 2016: 58 · 2015: 54 · 2014: 62 · 2013: 64 · 2012: 63
- FWCI
- 42.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Doris Duke Charitable Foundation
- Memorial Sloan-Kettering Cancer Center
- Academy of Finland
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL082677, K08HL082677)
- National Cancer Institute (CA10863101, R01CA101774, U24CA114737, U10CA021115)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- TET2 mutation, TET1, TET3, myeloid neoplasms, myeloproliferative neoplasms, chronic myelomonocytic leukemia, acute myeloid leukemia, somatic mutations, single nucleotide polymorphisms, promoter hypermethylation, overall survival, prognosis
- MeSH terms
- DNA-Binding Proteins, Exons, Humans, Mixed Function Oxygenases, Mutation, Myeloproliferative Disorders, Prognosis, Proto-Oncogene Proteins, Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic, Survival Rate, Case-Control Studies, Frameshift Mutation, Sequence Deletion, Codon, Nonsense, Mutation, Missense, Polymorphism, Single Nucleotide, Dioxygenases
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