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.
Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis / M. Caganova, C. Carrisi, G. Varano, F. Mainoldi, F. Zanardi, P. Germain, L. George, F. Alberghini, L. Ferrarini, A.K. Talukder, M. Ponzoni, G. Testa, T. Nojima, C. Doglioni, D. Kitamura, K. Toellner, I. Su, S. Casola. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 123:12(2013), pp. 5009-5022.
|Titolo:||Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis|
CAGANOVA, MARIETA (Primo)
|Parole Chiave:||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; Medicine (all)|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
Settore BIO/18 - Genetica
Settore MED/04 - Patologia Generale
|Data di pubblicazione:||2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI70626|
|Appare nelle tipologie:||01 - Articolo su periodico|