Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Abstract
Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.
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Loss-of-function mutations in other core PRC2 components EED and SUZ12 are seen in T-cell acute lymphoblastic leukaemia and malignant peripheral nerve sheath tumours.
“Loss-of-function mutations in other core PRC2 components EED and SUZ12 are also seen in T-cell acute lymphoblastic leukaemia and malignant peripheral nerve sheath tumours 153-155 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [153]
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- Authors
- Ernst, T., Chase, A. J., Score, J., Hidalgo-Curtis, C. E., Bryant, C., Jones, A. V., Waghorn, K., Zoi, K., Ross, F. M., Reiter, A., Hochhaus, A., Drexler, H. G., Duncombe, A., Cervantes, F., Oscier, D., Boultwood, J., Grand, F. H., & Cross, N. C. P.
- Affiliations
- University of Southampton (GB)
- Wessex Regional Genetics Laboratory (GB)
- Academy of Athens (GR)
- Heidelberg University (DE)
- Jena University Hospital (DE)
- Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures (DE)
- Southampton General Hospital (GB)
- Hospital Clínic de Barcelona (ES)
- Royal Bournemouth Hospital (GB)
- John Radcliffe Hospital (GB)
- Corresponding author
- Cross, Nicholas C P
- ORCID
- Venue
- Nature Genetics
- Published
- 2010-07-04
- Volume
- 42
- Issue
- 8
- Pages
- 722-726
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1963736125
- Cited by
- 1,139
- References
- 40
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 25 · 2023: 42 · 2022: 33 · 2021: 64 · 2020: 61 · 2019: 52 · 2018: 55 · 2017: 71 · 2016: 113 · 2015: 94 · 2014: 91 · 2013: 132 · 2012: 132
- FWCI
- 79.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- 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 › Chromatin Remodeling and Cancer
- Keywords
- EZH2, histone methyltransferase, somatic mutations, myeloid disorders, myelodysplastic/myeloproliferative neoplasms, myelofibrosis, chromosome 7q, uniparental disomy, polycomb repressive complex 2, H3K27 methylation, tumor suppressor, epigenetic repression
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Histone Methyltransferases, Cell Differentiation, DNA-Binding Proteins, Female, Genes, Regulator, Histones, Humans, Lysine, Male, Histone-Lysine N-Methyltransferase, Proteins, Transcription Factors, Genes, Tumor Suppressor, Polycomb Repressive Complex 2
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