BCL-W has a fundamental role in B cell survival and lymphomagenesis
Clare M. Adams, … , Jerald Z. Gong, Christine M. Eischen
Clare M. Adams, … , Jerald Z. Gong, Christine M. Eischen
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):635-650. https://doi.org/10.1172/JCI89486.
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Research Article Hematology Oncology

BCL-W has a fundamental role in B cell survival and lymphomagenesis

Abstract

Compromised apoptotic signaling is a prerequisite for tumorigenesis. The design of effective therapies for cancer treatment depends on a comprehensive understanding of the mechanisms that govern cell survival. The antiapoptotic proteins of the BCL-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Unlike BCL-2 and BCL-XL, the closest antiapoptotic relative BCL-W is required for spermatogenesis, but was considered dispensable for all other cell types. Here, however, we have exposed a critical role for BCL-W in B cell survival and lymphomagenesis. Loss of Bcl-w conferred sensitivity to growth factor deprivation–induced B cell apoptosis. Moreover, Bcl-w loss profoundly delayed MYC-mediated B cell lymphoma development due to increased MYC-induced B cell apoptosis. We also determined that MYC regulates BCL-W expression through its transcriptional regulation of specific miR. BCL-W expression was highly selected for in patient samples of Burkitt lymphoma (BL), with 88.5% expressing BCL-W. BCL-W knockdown in BL cell lines induced apoptosis, and its overexpression conferred resistance to BCL-2 family–targeting BH3 mimetics. Additionally, BCL-W was overexpressed in diffuse large B cell lymphoma and correlated with decreased patient survival. Collectively, our results reveal that BCL-W profoundly contributes to B cell lymphoma, and its expression could serve as a biomarker for diagnosis and aid in the development of better targeted therapies.

Authors

Clare M. Adams, Annette S. Kim, Ramkrishna Mitra, John K. Choi, Jerald Z. Gong, Christine M. Eischen

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