EZH2/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions

Enhancer of zeste homolog 2 (EZH2) and Bcl-2 gene rearrangement or protein upregulation played pivotal roles in the carcinogenesis of various malignancies including lymphomas. However, EZH2/Bcl-2 expression pattern and its clinicopathologic/prognostic significance in diffuse large B-cell lymphoma (DLBCL) remain unclear. To identify the association among EZH2, Bcl-2, clinicopathologic parametres in DLBCL, 2 DLBCL patient sets (test cohort, n=85; validation cohort n=51) and DLBCL cell lines were studied by tumor tissue microarray (TMA), immunohistochemistry and western blot. The optimal cut-off of EZH2 was determined by X-tile program from test cohort, as was verified in validation cohort. The prognostic significance was determined via Kaplan-Meier survival estimates and log-rank tests. Consequently, EZH2 and Bcl-2 expression were both enhanced and positively correlated with each other (𝑃=0.001) in both DLBCL patients and cell lines. EZH2/Bcl-2 coexpression was associated with poor overall survival (OS) and progression-free survival (PFS) in all DLBCL patients (all P<0.05). Univariate analyses revealed that EZH2/Bcl-2 coexpression correlated to worse objective response rate (ORR), shorter OS and PFS in DLBCL patients treated with RCHOP while multivariate analysis indicated that only elevated LDH level (P=0.001) and presence of B symtom (P=0.008) rather than EZH2/Bcl-2 coexpression were associated with worse OS. No survival benefit from rituximab regimen had been demonstrated in the early-staged DLBCL patients with EZH2/Bcl-2 coexpression. While in the subgroup of III-IV stage, RCHOP regimen showed obvious better OS and PFS than CHOP (P=0.039 and 0.005). In conclusion, EZH2/Bcl-2 coexpression defines unrecognized subgroup of DLBCL patients with distinct epigenetic phenotype and worse outcome.