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 5

Genome-wide identification and characterization of H3K27me3 and H3K4me3 target genes in mouse GC B cells.

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Genome-wide identification and characterization of H3K27me3 and H3K4me3 ...
(A) Venn diagram showing sets of genes marked by H3K27me3 and/or H3K4me3, respectively, in primary GC B cells purified from the spleens of immunized C57BL/6J wild-type mice. (B) Box plot of average mRNA levels of genes marked by H3K27me3 (n = 4,549), H3K4me3 (n = 6,311), or both histone marks (n = 1,747) in GC B cells. ***P < 2.2 × 10–16 (t test). (C) Box plot analysis of transcript levels of candidate genes (relative to Rplp0) quantified in Ezh2 control (Ezh2fl/+:Cγ1-cre [Ezh2+/–]; n = 15) and mutant (Ezh2fl/fl:Cγ1-cre [Ezh2–/–]; n = 17) primary GC B cells. P values are indicated within each plot (Wilcoxon rank-sum test). (B and C) In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate one and half time the value of the interquartile range added to the 75th percentile, or subtracted to the 25th percentile, respectively. (D) H3K27me3 status in wild-type GC B cells of 67 candidate genes (listed in Supplemental Table 2) tested by qRT-PCR in Ezh2 control and mutant GC B cells described in C. The genes were grouped based on whether expression was upregulated (up) or remained unchanged (no change) in Ezh2 mutant GC B cells. ***P = 0.0009 (Fisher’s exact test).