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

Abstract

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.

Impact of Genetic Polymorphism of Myeloid Differentiation Primary Response Gene 88, Enhancer of Zeste Homolog 2, and B-cell Lymphoma 2 like 11 in Patients with Diffuse Large B Cell Lymphoma Treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristin

“…Although some studies suggested that EZH2 mutations are associated with resistance to R-CHOP regimen [23], in our study, there was no significant correlation between response to R-CHOP therapy or survivals with either EZH2 or BCL2L11 polymorphisms. This is in contrary with findings by Deng et al who found that EZH2/Bcl-2 coexpression correlated to worse objective response rate in DLBCL patients [24]. On the other hand, Cummin et al found that overall outcomes are similar in mutant and wild-type EZH2 mutations when adjusted for COO and IPI [25].…”

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

“…Moreover, it has recently been described that MELK interacts with the transcription factor FOXM1 (a master regulator for cell proliferation) in a Plk-1-dependent manner and that EZH2-mediated radiation resistance occurs through a MELK-FOXM1-dependent manner in glioblastoma cells 9,44 . FOXM1, Plk-1, and EZH2 are all described as interesting therapeutic targets in both DLBCL and MCL, and high expression of these genes is reported to be associated with poor survival in lymphoma patients [45][46][47][48] .…”

5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients

“…The International Prognostic Index (IPI) is the primary prognostic risk assessment method for DLBCL, especially in high-risk patients, and is used for R-CHOP chemotherapies [ 8 – 10 ]. However, IPI cannot accurately predict the therapeutic effect of R-CHOP in DLBCL patients [ 11 ]. Furthermore, recent studies have demonstrated that the detection of the apoptosis inhibitor, survivin [ 12 ], activation­induced cytidine deaminase (AID) [ 13 ], plasma miRNA [ 14 ], exosome miRNA [ 15 ], and genes polymorphism [ 16 , 17 ], as well as the presence of CD3 and FoxP3 in the immune microenvironment [ 18 ], were all potential indicators of treatment efficacy in DLBCL patients.…”