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Title: Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis
Authors: Su, I-hsin
Talukder, Asoke K.
Nojima, Takuya
Doglioni, Claudio
Kitamura, Daisuke
Toellner, Kai-M
Casola, Stefano
Caganova, Marieta
Carrisi, Chiara
Varano, Gabriele
Mainoldi, Federica
Zanardi, Federica
Germain, Pierre-Luc
George, Laura
Alberghini, Federica
Ferrarini, Luca
Ponzoni, Maurilio
Testa, Giuseppe
Keywords: DRNTU::Science::Biological sciences::Molecular biology
Issue Date: 2013
Source: Caganova, M., Carrisi, C., Varano, G., Mainoldi, F., Zanardi, F., Germain, P. L., et al. (2013). Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. Journal of Clinical Investigation, 1-14.
Series/Report no.: Journal of clinical investigation
Abstract: Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte–induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.
ISSN: 0021-9738
DOI: 10.1172/JCI70626
Rights: © 2013 The American Society for Clinical Investigation. This paper was published in Journal of Clinical Investigation and is made available as an electronic reprint (preprint) with permission of The American Society for Clinical Investigation. The paper can be found at the following official DOI: [].  One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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