Biological functions of EZH2 in normal B-cell development and lymphomagenesis. During B-cell differentiation, naive B cells enter the GC and EZH2 is transcriptionally upregulated during GC B-cell maturation.^26,47  Via induction of H3K27me3, EZH2 then transcriptionally represses a myriad of downstream effector genes, which at least include the negative cell-cycle regulators (CDKN2A and CDKN1A) and B-cell differentiation-promoting transcription factors (IRF4 and BLIMP1/PRDM1), hence allowing for rapid expansion of immature B cells^47,56,57 ; in addition, EZH2 protects GC B cells from the genotoxic damages induced by activation-induced cytidinedeaminase (AID),⁴⁷  an enzyme critical for immunoglobulin affinity maturation via a mechanism of somatic hypermutation that modifies the immunoglobulin variable region of the rearranged antibody genes in GC B cells.²¹  EZH2 levels decrease as B cells exit the GC, enabling derepression of EZH2-targeted genes and hence terminal differentiation.^47,56,57  However, EZH2 hyperactivity (either somatic mutation or overexpression) disrupts such fine equilibrium, continuously enhances H3K27me3, and results in exaggerated silencing of EZH2 targeted genes, which then block GC B-cell differentiation and promote their proliferation and survival. EZH2 mutations alone lead to follicular hyperplasia, and, with acquisition of additional oncogenic events such as upregulation of BCL2 or c-MYC, EZH2 mutations cooperatively enable or accelerate malignant transformation of GC B cells.^56,58