Targeting the neomorphic EZH2 function in lymphomas. (A) EZH2 hotspot mutations promote the trimethylation of H3K27 leading to global H3K27me3 accumulation in mutant cells. This enhances suppression of PRC2 targets through epigenetic silencing. Treatment with tazemetostat blocks methylation of H3K27 leading to a global reduction in H3K27Me3. Question mark (?) denotes that the exact methylation state of H3K27 in cells treated with tazemetostat is currently unknown. (B) Malignant cells bearing EZH2 mutations have reduced expression of genes associated with differentiation and major histocompatibility complex (MHC) expression. Treatment with tazemetostat can release these genes from epigenetic silencing and reverse both phenotypes, leading to differentiation and possibly cell death and/or reexpression of MHC, allowing recognition by T cells. This is known in DLBCL and hypothesized in FL. (C) Phase 1/2 trial design of tazemetostat in B-NHL. MUT, mutant; ORR, overall response rate; PD, pharmacodynamics; PK, pharmacokinetics; SAM, s-adenosyl methionine; WT, wild type. Illustration created with BioRender.com.