Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis

Marieta Caganova, Chiara Carrisi, Gabriele Varano, Federica Mainoldi, Federica Zanardi, Pierre Luc Germain, Laura George, Federica Alberghini, Luca Ferrarini, Asoke K. Talukder, Maurilio Ponzoni, Giuseppe Testa, Takuya Nojima, Claudio Doglioni, Daisuke Kitamura, Kai M. Toellner, I. Hsin Su, Stefano Casola

Research output: Contribution to journalArticlepeer-review

Abstract

Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, whichare 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.

Original languageEnglish
Pages (from-to)5009-5022
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
Publication statusPublished - Dec 2 2013

ASJC Scopus subject areas

  • Medicine(all)

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