Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW

Abstract

Purpose B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an anti-apoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other anti-apoptotic BCL2 family members in six different B-cell lymphomas. Experimental Design We performed a large-scale gene expression analysis of data sets comprising approximately 2300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as indolent and aggressive lymphomas. Data were validated experimentally with qRT-PCR and immunohistochemistry. Results We report BCLW is significantly overexpressed in aggressive and indolent lymphomas, including DLBCL, Burkitt, follicular, mantle cell, marginal zone, and Hodgkin lymphomas. Notably, BCLW was preferentially overexpressed over that of BCL2 and negatively correlated with BCL2 in specific lymphomas. Unexpectedly, BCLW was overexpressed as frequently as BCL2 in follicular lymphoma. Evaluation of all five anti-apoptotic BCL2 family members in six types of B-cell lymphoma revealed that BCL2, BCLW, and BCLX were consistently overexpressed, whereas MCL1 and A1 were not. Additionally, individual lymphomas frequently overexpressed more than one anti-apoptotic BCL2 family member. Conclusions Our comprehensive analysis indicates B-cell lymphomas commonly select for BCLW overexpression in combination with or instead of other anti-apoptotic BCL2 family members. Our results suggest BCLW is likely equally as important in lymphomagenesis as BCL2 and that targeting BCLW in lymphomas should be considered.

BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

“…Although the role of other anti-apoptotic proteins in the pathogenesis of B-NHL is less clear, it is probable that various B-NHL subtypes rely on more than one anti-apoptotic protein [52]. The potential role of MCL-1 in lymphoma pathogenesis was demonstrated in transgenic mouse models in which MCL-1 transgenic mice developed B-cell lymphomas at high frequency [53].…”

“…Moreover, BCL-XL is critical for the proper development of platelets, and targeted inhibition of BCL-XL has been associated with thrombocytopenia (see Section 5.). Another anti-apoptotic protein, BCL-W has been shown to be overexpressed in the majority of aggressive and indolent lymphoma, including DLBCL (equally in both COO subtypes), BL, MCL, FL, and MZL, making it a potential therapeutic target in B-NHL [52].…”

IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

“…We collected the data from gene expression omnibus (GEO) (22) or the authors' Web site (23). The GEO identifications for CLL data are the following: GSE26725, GSE50006, GSE16455, GSE26526, GSE21029, GSE69034, GSE49896, GSE39671, GSE9250, and GSE22762, and the datasets for the six lymphoma types and normal samples are previously described (24). The data were generated on the Affymetrix Human Genome U133 Plus 2.0 platform following the standard Affymetrix protocol.…”

Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance

“…As a consequence, elevated levels of BCL-2 are observed in both DLBCL subtypes. Nevertheless, BCL-2 is more abundantly expressed in the ABC-than the GCBsubtype 28 . Besides BCL-2 translocation and amplification, BCL-2 gene rearrangement is reported in double-hit lymphomas, which represent~10% of DLBCL.…”