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 2

MYC-induced apoptosis is augmented by loss of Bcl-w.

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MYC-induced apoptosis is augmented by loss of Bcl-w. (A–E) BM-derived pr...
(A–E) BM-derived pre–B cells from Bcl-w+/+, Bcl-w+/–, and Bcl-w–/– littermates were infected with the 4-OHT–inducible MYCER. Western blot analysis was performed (A). Equal numbers of cells of each genotype were placed into culture. Following the addition of 4-OHT to activate MYCER, MTS assays (A) were performed in quadruplicate, total viable cell numbers (B) and viability (C) were determined using trypan blue dye (in triplicate), and annexin V positivity (in triplicate) (D) and caspase 3 cleavage (CC3) (E) were evaluated. (F–J) BM from Bcl-w+/+ Eμ-MYC, Bcl-w+/– Eμ-MYC, and Bcl-w–/– Eμ-MYC–Tg littermates prior to any detectable lymphoma was placed into culture on day 0, and cells were counted at intervals. Western blot analysis was performed on the pre–B cells that grew out of the cultures (F). Population doublings were calculated (F) and viability was determined by trypan blue dye exclusion (G). (H) Equal numbers of pre–B cells of each genotype were plated and MTS assays (quadruplicate) performed. (I and J) At the indicated intervals, cells were collected and annexin V positivity (I) and cleaved caspase 3 (J) assessed. Data shown are representative of 3 to 4 independent experiments using cells isolated from 3 separate litters generated by different parents. Error bars indicate the SD. *P < 0.0001 for A, *P < 0.029 for B, *P < 0.003 for C, *P < 0.028 for D (comparing 4-OHT–treated samples), *P < 0.0001 for H, and *P < 0.0002 for I, by 1-way ANOVA.