EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
Abstract
In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.
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PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.
“More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [172]
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- Authors
- McCabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., Liu, Y., Graves, A. P., III, A. D. P., Diaz, E., LaFrance, L. V., Mellinger, M., Duquenne, C., Tian, X., Kruger, R. G., McHugh, C. F., Brandt, M., Miller, W. H., Dhanak, D., Verma, S. K., Tummino, P. J., & Creasy, C. L.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Creasy, Caretha L.
- ORCID
- Venue
- Nature
- Published
- 2012-10-10
- Volume
- 492
- Issue
- 7427
- Pages
- 108-112
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2004380688
- Cited by
- 1,786
- References
- 31
- Citations by year
- 2026: 34 · 2025: 89 · 2024: 80 · 2023: 123 · 2022: 99 · 2021: 119 · 2020: 119 · 2019: 147 · 2018: 131 · 2017: 161 · 2016: 171 · 2015: 178 · 2014: 185 · 2013: 134 · 2012: 15
- FWCI
- 66.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- GlaxoSmithKline
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- EZH2 inhibition, diffuse large B-cell lymphoma, follicular lymphoma, polycomb repressive complex 2, H3K27 methylation, GSK126, histone methylation, xenograft tumor growth
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Histone Methyltransferases, Animals, Histones, Humans, Indoles, Lymphoma, Follicular, Methylation, Mutation, Neoplasm Transplantation, Histone-Lysine N-Methyltransferase, Pyridones, Repressor Proteins, Transplantation, Heterologous, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, Gene Silencing, Cell Line, Tumor, Cell Proliferation, Mice, Polycomb Repressive Complex 2
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Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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