The ability of the immune system to fend off specific pathogens following immunization depends the generation high-affinity antibody producing plasma cells (PCs) and long-lived memory B cells. Both PCs and B cells differentiate in germinal centers (GCs) within lymphoid tissue. Many B cell malignancies, including lymphoma, are the result of GC dysfunction; however the factors that regulate the GC response are poorly understood. Given that the histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in human GC B cells, Marieta Caganova and colleagues from the Italian Foundation for Cancer Research evaluated the contribution of EZH2 to the maintenance of GC function. Lack of EZH2 in mouse B cells reduced the number of B cells in GCs, which led to poor antibody responses and fewer memory B cells. Furthermore, the absence of EZH2 increased apoptosis and sensitivity to genotoxic damage. GC-derived Non-Hodgkin lymphoma is associated with gain of function mutations in EZH2, and inhibition of EZH2 in NHL cells impaired growth. These data indicate that EZH2 function to maintain GC responses. The accompanying micrograph shows EZH2 expression (brown) in germinal centers of reactive lymph nodes.
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
Marieta Caganova, Chiara Carrisi, Gabriele Varano, Federica Mainoldi, Federica Zanardi, Pierre-Luc Germain, Laura George, Federica Alberghini, Luca Ferrarini, Asoke K. Talukder, Maurilio Ponzoni, Giuseppe Testa, Takuya Nojima, Claudio Doglioni, Daisuke Kitamura, Kai-M. Toellner, I-hsin Su, Stefano Casola