Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.
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 t...
| Publicado en: | Journal of Clinical Investigation Vol. 123; no. 12; pp. 5009 - 5023 |
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| Autores principales: | , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
American Society for Clinical Investigation
Dec2013
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104120996&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104120996 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00219738 0YX jtl: Journal of Clinical Investigation issn: 00219738 maglogo: N pubinfo: dt: Dec2013 vid: 123 iid: 12 pid: 11983 pub: American Society for Clinical Investigation place: Ann Arbor, Michigan artinfo: ui: 104120996 NLM24200695 2012401636 10.1172/JCI70626 NLM24200695 PMC3859423 104120996 ppf: 5009 ppct: 14 formats: tig: atl: Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. aug: au: Caganova, Marieta Carrisi, Chiara Varano, Gabriele Mainoldi, Federica Zanardi, Federica Germain, Pierre-Luc George, Laura Alberghini, Federica Ferrarini, Luca Talukder, Asoke K Ponzoni, Maurilio Testa, Giuseppe Nojima, Takuya Doglioni, Claudio Kitamura, Daisuke Toellner, Kai-M Su, I-Hsin Casola, Stefano sug: subj: B Lymphocytes Immunology Lymphoid Tissue Lymphoma, Non-Hodgkin's Etiology Proteins Physiology Animal Studies Antibody Formation Apoptosis B Lymphocytes Pathology Biochemical Phenomena Cell Cycle DNA Genes Genetics Hematopoiesis Hydrolases Hydrolases Deficiency Hydrolases Physiology Immunity Lymphoid Tissue Immunology Lymphoid Tissue Pathology Lymphoma, Non-Hodgkin's Lymphoma, Non-Hodgkin's Pathology Methylation Mice Proteins Funding Source ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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