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

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.