Abstract
BCL-W prevents lymphocyte apoptosis and is negatively regulated by MYC-induced miR-15 family members.
Major finding: BCL-W prevents lymphocyte apoptosis and is negatively regulated by MYC-induced miR-15 family members.
Clinical relevance: BCL-W is highly expressed in patients with Burkitt lymphoma and DLBCL and linked to poor survival.
Impact: BCL-W may be a potential therapeutic target to induce apoptosis in patients with B-cell lymphoma.
The antiapoptotic BCL2 proteins, including BCL2 and BCL-XL, are often overexpressed in cancer and promote cell survival. The antiapoptotic BCL2 protein BCL-W has a crucial role in spermatogenesis, but its role in tumorigenesis is not clear, prompting Adams and colleagues to investigate its role in lymphoma. BCL-W was expressed in lymphocytes, and loss of expression promoted apoptosis in response to cytokine deprivation or MYC activation, indicating an essential role for BCL-W in lymphocyte survival. In vivo, BCL-W loss delayed lymphoma growth and extended survival in a mouse model of MYC-driven B-cell lymphoma. BCL-W expression was negatively regulated by MYC, which induced transcription of miR-15 family members that bound directly to BCL-W to reduce its expression and thereby promote apoptosis. Consistent with these findings, depletion of BCL-W, via BCL-W shRNA or overexpression of miR-15a, induced apoptosis in Burkitt lymphoma cell lines, suggesting the possibility for therapeutic targeting of BCL-W in Burkitt lymphoma. In addition, pharmacologic inhibition of BCL-W with the BH3 mimetic compounds ABT-737 and ABT-263 induced apoptosis in Burkitt lymphoma cells, which could be prevented by overexpression of BCL-W. Moreover, BCL-W was overexpressed in patients with Burkitt lymphoma, whereas miR-15a was expressed at low levels, further indicating that BCL-W may contribute to Burkitt lymphoma pathogenesis. BCL-W was also overexpressed in diffuse large B-cell lymphoma (DLBCL) cell lines and patient samples, and its overexpression was correlated with a poorer survival in patients, suggesting that BCL-W may also contribute to DLBCL. Taken together, these findings indicate that BCL-W enhances cell survival to promote B-cell lymphoma, and suggest that BCL-W may be useful as a prognostic biomarker or therapeutic target in patients with B-cell lymphoma.
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