Abstract 02: BCL-W significantly contributes to B-cell lymphoma survival and development

Abstract

Abstract The ability of cells to undergo apoptosis in response to cellular stresses functions as a safeguard against tumorigenesis. Consequently, compromised apoptotic signaling must precede tumor development. To design effective therapies for cancer treatment, the underlying mechanisms that govern cell survival need to be understood. The anti-apoptotic proteins of the Bcl-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Bcl-w, the closest anti-apoptotic relative to Bcl-2 and Bcl-xL, is essential for spermatogenesis, but was considered dispensable for other cell types. However, we recently uncovered a significant role for Bcl-w in B-cell survival and lymphomagenesis. Specifically, loss of Bcl-w conferred sensitivity to growth factor deprivation-induced B-cell apoptosis. In addition, apoptosis triggered by hyperproliferative signals from the Myc oncogene was accentuated by loss of Bcl-w. Consequences of elevated apoptosis were observed in vivo, as Bcl-w loss profoundly delayed Myc-mediated B-cell lymphoma development. We also determined Myc regulates Bcl-w expression through its transcriptional regulation of the miR-15 family. Importantly, evaluation of Burkitt lymphoma (BL) patient samples revealed BCL-W overexpression was highly selected for, and that targeting BCL-W using multiple methods induced apoptosis of BL cells. In addition, overexpression of BCL-W in BL cell lines conferred resistance to the BH3-mimetics ABT-737 and ABT-263 that inhibit anti-apoptotic BCL-2 family members. Furthermore, BCL-W was overexpressed in diffuse large B-cell lymphoma (DLBCL) and correlated with decreased patient survival. Analysis of multiple data sets of other aggressive and indolent B-cell lymphomas showed that BCL-W was frequently overexpressed in them as well. Collectively, our data indicate that BCL-W is an understudied contributor to B-cell lymphoma development and survival that appears to be as important as BCL-2 to B-cell lymphomas. In addition, BCL-W is a predictive biomarker that could improve prognostication and the development of more effective treatment strategies for B-cell lymphomas. Citation Format: Clare M. Adams, Ramkrishna Mitra, Jerald Z. Gong, Annette S. Kim, John K. Choi, Christine M. Eischen. BCL-W significantly contributes to B-cell lymphoma survival and development [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 02.