Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis
Marieta Caganova, … , I-hsin Su, Stefano Casola
Marieta Caganova, … , I-hsin Su, Stefano Casola
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5009-5022. https://doi.org/10.1172/JCI70626.
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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

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

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Figure 9

Y641 mutant of EZH2 silences BLIMP1 expression through PRC2 to facilitate DLBCL growth.

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Y641 mutant of EZH2 silences BLIMP1 expression through PRC2 to facilitat...
(A) BLIMP1 transcripts in SU-DHL-4 and SU-DHL-6 DLBCL cells 12 days after treatment with GSK343 or vehicle, as revealed by qRT-PCR analysis. Columns indicate mean ± SD of triplicates. Expression is relative to that of vehicle-treated control cells after normalization for RPLP0 expression. (B) Growth curves of SU-DHL-4 (black line) and SU-DHL-6 (gray line) DLBCL cells treated with either GSK343 (solid line) or vehicle (dotted line). Average cell numbers at the indicated time points ± SEM of 4 replicates is shown. ***P < 0.001 (2-way ANOVA). (C) BLIMP1 transcript levels in SU-DHL-4 DLBCL cells after infection with lentiviruses expressing control (ctrl) or anti-EED (EED) shRNAs, respectively. Results are presented relative to control after normalization for GAPDH expression. Columns indicate mean of 2 independent experiments. (D) Frequency of SU-DHL-4 DLBCL cells expressing shRNA against EED relative to those expressing control shRNA at the indicated days after lentivirus infection. (E) qRT-PCR analysis of Blimp1 transcript levels in WSU-DLCL-2 DLBCL cells transfected with control or BLIMP1 expression vector, respectively. Columns indicate mean value of 2 independent experiments. Values are presented relative to control after normalization for HPRT expression. (F) Comparison of WSU-DLCL-2 cell numbers at the indicated days after transfection with control or Blimp1 expression vector, respectively. Data are representative of 2 experiments.