Journal Article

Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis

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

2013

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antibodies / Apoptosis / B cells / B-Lymphocytes - immunology / B-Lymphocytes - pathology / Biomedical research / Cell Cycle / Cytidine Deaminase - deficiency / Cytidine Deaminase - genetics / Cytidine Deaminase - physiology / DNA Damage / Enhancer of Zeste Homolog 2 Protein / Enzyme Activation / Gene Expression Regulation, Neoplastic / Gene Rearrangement, B-Lymphocyte, Heavy Chain / Gene Silencing / Genetic aspects / Germinal Center - enzymology / Germinal Center - immunology / Germinal Center - pathology / Immune system / Immunity, Humoral / Immunologic Memory / Immunology / Lymphoma, Non-Hodgkin - enzymology / Lymphoma, Non-Hodgkin - etiology / Lymphoma, Non-Hodgkin - genetics / Lymphoma, Non-Hodgkin - pathology / Lymphopoiesis / Medical research / Methylation / Mice / Mice, Transgenic / Mutation / Non-Hodgkin's lymphomas / Physiological aspects / Polycomb Repressive Complex 2 - deficiency / Polycomb Repressive Complex 2 - genetics / Polycomb Repressive Complex 2 - physiology / Positive Regulatory Domain I-Binding Factor 1 / Protein Processing, Post-Translational / Transcription Factors - physiology / Viral antibodies