Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.
Research paper by
Marieta M Caganova, Chiara C Carrisi, Gabriele G Varano, Federica F Mainoldi, Federica F Zanardi, Pierre-Luc PL Germain, Laura L George, Federica F Alberghini, Luca L Ferrarini, Asoke K AK Talukder, Maurilio M Ponzoni, Giuseppe G Testa, Takuya T Nojima, Claudio C Doglioni, Daisuke D Kitamura, Kai-M KM Toellner, I-hsin IH Su, Stefano S Casola
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.