1. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
- Author
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Ryan G. Kruger, William H. Miller, Louis V. LaFrance, Celine Duquenne, Alan P. Graves, Heidi M. Ott, Dashyant Dhanak, Christine Thompson, Xinrong Tian, Martin Brandt, Michael T. McCabe, Charles F. McHugh, Mellinger Mark, Susan Korenchuk, Anthony Della Pietra, Peter J. Tummino, Yan Liu, Caretha L. Creasy, Sharad K. Verma, Elsie Diaz, Gopinath Ganji, and Glenn S. Van Aller
- Subjects
Regulation of gene expression ,Multidisciplinary ,Methyltransferase ,biology ,EZH2 ,Mutant ,macromolecular substances ,medicine.disease_cause ,Histone H3 ,Histone methyltransferase ,medicine ,biology.protein ,Cancer research ,Carcinogenesis ,PRC2 - Abstract
EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). Overexpression of EZH2 is implicated in tumorigenesis, and mutations within its catalytic domain occur in lymphoma. Here, Caretha Creasy and colleagues describe a potent small-molecule inhibitor of EZH2 methyltransferase activity that decreases levels of methylated H3K27 and reactivates silenced PRC2 target genes. It also inhibits the proliferation of EZH2 mutant cell lines and the growth of EZH2 mutant xenografts in mice. Pharmacological inhibition of EZH2 activity may therefore be a viable strategy for treating EZH2 mutant lymphoma.
- Published
- 2012
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