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 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.