1. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation.
- Author
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Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN, Wang L, Ezponda T, Martinez-Garcia E, Zhang H, Zheng Y, Verma SK, McCabe MT, Ott HM, Van Aller GS, Kruger RG, Liu Y, McHugh CF, Scott DW, Chung YR, Kelleher N, Shaknovich R, Creasy CL, Gascoyne RD, Wong KK, Cerchietti L, Levine RL, Abdel-Wahab O, Licht JD, Elemento O, and Melnick AM
- Subjects
- Animals, Cell Differentiation, Cell Proliferation, Enhancer of Zeste Homolog 2 Protein, Gene Deletion, Gene Expression Regulation, Neoplastic, Germinal Center drug effects, Histones metabolism, Methylation, Mice, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 metabolism, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-2 physiology, B-Lymphocytes metabolism, Cell Transformation, Neoplastic genetics, Germinal Center metabolism, Mutation, Polycomb Repressive Complex 2 physiology
- Abstract
The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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