title: Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.
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.
authors.forename: Marieta
authors.initials: M
authors.lastname: Caganova
authors.forename: Chiara
authors.initials: C
authors.lastname: Carrisi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varano
authors.forename: Federica
authors.initials: F
authors.lastname: Mainoldi
authors.forename: Federica
authors.initials: F
authors.lastname: Zanardi
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Germain
authors.forename: Laura
authors.initials: L
authors.lastname: George
authors.forename: Federica
authors.initials: F
authors.lastname: Alberghini
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrarini
authors.forename: Asoke K
authors.initials: AK
authors.lastname: Talukder
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Testa
authors.forename: Takuya
authors.initials: T
authors.lastname: Nojima
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.forename: Kai-M
authors.initials: KM
authors.lastname: Toellner
authors.forename: I-hsin
authors.initials: IH
authors.lastname: Su
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002453:Cell Cycle; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D000071221:Enhancer of Zeste Homolog 2 Protein; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D020868:Gene Silencing; D018858:Germinal Center / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D056724:Immunity, Humoral; D007156:Immunologic Memory; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D038041:Lymphopoiesis; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000502:physiology
chemical_list: C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D003564:Cytidine Deaminase