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

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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.

Original languageEnglish
Pages (from-to)5009-5022
Number of pages14
JournalJournal of Clinical Investigation
Issue number12
Early online date8 Nov 2013
Publication statusPublished - Dec 2013


  • Animals
  • Apoptosis
  • B-Lymphocytes
  • Cell Cycle
  • Cytidine Deaminase
  • DNA Damage
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Gene Silencing
  • Germinal Center
  • Immunity, Humoral
  • Immunologic Memory
  • Lymphoma, Non-Hodgkin
  • Lymphopoiesis
  • Methylation
  • Mice
  • Mice, Transgenic
  • Polycomb Repressive Complex 2
  • Protein Processing, Post-Translational
  • Transcription Factors


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