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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Figure 8

Increased expression of BCL-W confers resistance to BL cells to BH3 mimetics.

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Increased expression of BCL-W confers resistance to BL cells to BH3 mime...
(A) The IC50 of the BH3 mimetics ABT-737 and ABT-263 for 2 human BL cell lines (Daudi and Ramos) was determined using MTS assays (in quadruplicate, 48 h). (B–E) Daudi cells remained uninfected (Un) or were retrovirally infected to express empty vector (Vec), BCL-W (BW), or BCL-2 (B2). Following treatment with ABT-737 (+), ABT-263 (+), or DMSO vehicle control (–) at the determined IC50 (B–D) or the indicated concentrations (E) for 48 hours (B, C, and E) or the indicated intervals (D), Western blotting for cleaved caspase 3 (B) and MTS assays (C–E, in quadruplicate) were performed. Data shown are representative of 2 independent experiments for both inhibitors. For data in D and E, experiments with inhibitors were performed at the same time but graphed separately, thus the DMSO control data are the same. Error bars indicate the SD. *P < 6.67 × 10–6 ABT-737 and #P < 6.05 × 10–5 ABT-263 (ABT vs. DMSO) (C); *P < 2.69 × 10–4 ABT-737 and #P < 3.7 × 10–4 ABT-263 (vector with ABT vs. vector, BCL-W, or BCL-2 with DMSO) (D); *P < 7.33 × 10–4 ABT-737 and #P < 0.011 ABT-263 (BCL-W or BCL-2 with ABT vs. BCL-W or BCL-2 with DMSO) (E), by t test.