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 6

BCL-W expression is selected for in human BL.

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BCL-W expression is selected for in human BL. (A) qRT-PCR analysis (in t...
(A) qRT-PCR analysis (in triplicate) of samples from patients with BL (n = 15) compared with normal lymphoid control tissue (n = 7). mRNA levels were normalized to β-actin and presented as 2–ΔΔCt. Bars represent the mean ± SEM. *P = 9.1 × 10–4, by t test. (B) Microarray gene expression–profiling data for BCL-W and BCL-2 mRNA in BL (n = 57) compared with normal B cells (n = 49). Bars represent the mean ± SEM. Each circle represents 1 sample, and the y axis represents normalized expression of BCL-W and BCL-2. *P = 1.8 × 10–8, by t test. The data sets analyzed are listed in Supplemental Table 1. (C) Immunohistochemical analysis for BCL-W and BCL-2 protein was performed on samples from patients with BL (n = 26). Box and whisker plots of pathologist scores and representative images of BCL-W and BCL-2 staining from the same tumor sample are shown. Original magnification, ×40; scale bars: 200 μm. *P < 0.0001, by t test. For the box and whisker plots, the box represents the 25th and 75th percentiles, the line indicates the median, the circle indicates the mean, and the whiskers represent the maximum and minimum. (D) Protein expression was assessed by Western blotting for the indicated proteins in BL and DLBCL cell lines. Controls included tissue from 2 human spleens and purified B cells from human peripheral blood.