期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 12, 页码 5009-5022出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI70626
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资金
- FIRC
- Umberto Veronesi Foundation
- Association for International Cancer Research
- Italian Association for Cancer Research
- Italian Ministry of Health through FIRB IDEAS
- CARIPLO Foundation
- Giovanni Armenise-Harvard Foundation
- Italian Ministry of Health through Progetto Giovani Ricercatori
- Medical Research Council [G1001390] Funding Source: researchfish
- MRC [G1001390] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [25293116, 25118730, 24659225, 25111512] Funding Source: KAKEN
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.
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