Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms
Abstract
The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
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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 [155]
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“Mutations in other PRC2 components are rare in myeloid malignancies, but have recently been reported for SUZ12 and EED in MDS (Puda et al., 2012; Score et al., 2012).”
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- Authors
- Score, J., Hidalgo-Curtis, C., Jones, A. V., Winkelmann, N., Skinner, A., Ward, D., Zoi, K., Ernst, T., Stegelmann, F., Döhner, K., Chase, A., & Cross, N. C. P.
- Affiliations
- Wessex Regional Genetics Laboratory (GB)
- Academy of Athens (GR)
- Jena University Hospital (DE)
- University Hospital Ulm (DE)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-02-02
- Volume
- 119
- Issue
- 5
- Pages
- 1208-1213
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2048356390
- Cited by
- 177
- References
- 36
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 12 · 2019: 10 · 2018: 13 · 2017: 15 · 2016: 22 · 2015: 18 · 2014: 16 · 2013: 20 · 2012: 30
- FWCI
- 14.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- North Carolina Pork Council
- 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
- polycomb repressive complex 2, EZH2, SUZ12, EED, JARID2, myelodysplastic syndrome, myeloproliferative neoplasms, myelofibrosis, uniparental disomy, missense mutations, histone H3 lysine 27 methylation, myeloid disorders
- MeSH terms
- Aged, Aged, 80 and over, Amino Acid Sequence, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Myeloproliferative Disorders, Repressor Proteins, Cohort Studies, Sequence Homology, Amino Acid, Bone Marrow Neoplasms, Gene Silencing, Myelodysplastic-Myeloproliferative Diseases, Polycomb-Group Proteins
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