Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1-targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit.
Bibliographical noteFunding Information:
This work was supported by funding from the Victorian Cancer Agency Fellowship (MCRF 17028) (G.L.K.), Cancer Council Victoria, grants-in-aid #1086157 and #1147328 (G.L.K.), the National Health and Medical Research Council (grant 1086291) (G.L.K.), Program grant 101671 (A.S.), Fellowship 1020363 (A.S.), Leukaemia Foundation Australia grant (G.L.K. and A.S.), Leukaemia and Lymphoma Society (grant 7001-13) (A.S.), the estate of Anthony (Toni) Redstone OAM, The Craig Perkins Cancer Research Foundation, and operational infrastructure grants through the Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support.
Conflict-of-interest disclosure: The Walter and Eliza Hall Institute receives milestone and royalty payments related to venetoclax, and employees (S.T.D., C.C., L.T., J.-n.G., A.S., and G.L.K.) may be eligible for benefits related to these payments. The laboratory of A.S. receives research funding from Servier. The remaining authors declare no competing financial interests.
© 2020 by The American Society of Hematology.
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