TitleEZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation.
Publication TypeJournal Article
Year of Publication2013
AuthorsB├ęguelin, Wendy, Popovic Relja, Teater Matt, Jiang Yanwen, Bunting Karen L., Rosen Monica, Shen Hao, Yang Shao Ning, Wang Ling, Ezponda Teresa, Martinez-Garcia Eva, Zhang Haikuo, Zheng Yupeng, Verma Sharad K., McCabe Michael T., Ott Heidi M., Van Aller Glenn S., Kruger Ryan G., Liu Yan, McHugh Charles F., Scott David W., Chung Young Rock, Kelleher Neil, Shaknovich Rita, Creasy Caretha L., Gascoyne Randy D., Wong Kwok-Kin, Cerchietti Leandro, Levine Ross L., Abdel-Wahab Omar, Licht Jonathan D., Elemento Olivier, and Melnick Ari M.
JournalCancer Cell
Volume23
Issue5
Pagination677-92
Date Published2013 May 13
ISSN1878-3686
KeywordsAnimals, B-Lymphocytes, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Enhancer of Zeste Homolog 2 Protein, Gene Deletion, Gene Expression Regulation, Neoplastic, Germinal Center, Histones, Methylation, Mice, Mutation, Polycomb Repressive Complex 2, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-2
Abstract

<p>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.</p>

DOI10.1016/j.ccr.2013.04.011
Alternate JournalCancer Cell
PubMed ID23680150
PubMed Central IDPMC3681809
Grant ListR01 CA122794 / CA / NCI NIH HHS / United States
CA143879 / CA / NCI NIH HHS / United States
K08 CA160647 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
T32 CA070085 / CA / NCI NIH HHS / United States
1K08CA160647-01 / CA / NCI NIH HHS / United States
R01 CA143032 / CA / NCI NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
U54 CA143869 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States