BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Sarah T Diepstraten; Catherine Chang; Lin Tai; Jia-Nan Gong; Ping Lan; Alexander C Dowell; Graham S Taylor; Andreas Strasser; Gemma L Kelly

doi:10.1182/bloodadvances.2019000541

BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Sarah T Diepstraten, Catherine Chang, Lin Tai, Jia-Nan Gong, Ping Lan, Alexander C Dowell, Graham S Taylor, Andreas Strasser, Gemma L Kelly

Immunology and Immunotherapy

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Abstract

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.

Original language	English
Pages (from-to)	356-366
Number of pages	11
Journal	Blood Advances
Volume	4
Issue number	2
Early online date	27 Jan 2020
DOIs	https://doi.org/10.1182/bloodadvances.2019000541
Publication status	Published - 28 Jan 2020

Bibliographical note

Funding 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.

Funding Information:
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.

Publisher Copyright:
© 2020 by The American Society of Hematology.

ASJC Scopus subject areas

Hematology

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10.1182/bloodadvances.2019000541Licence: None: All rights reserved

Diepstraten_et_al_BCL-W_is_dispensible_Blood_Advances_2020
© 2020 by The American Society of Hematology Sarah T. Diepstraten, Catherine Chang, Lin Tai, Jia-nan Gong, Ping Lan, Alexander C. Dowell, Graham S. Taylor, Andreas Strasser, Gemma L. Kelly; BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines. Blood Adv 2020; 4 (2): 356–366. doi: https://doi.org/10.1182/bloodadvances.2019000541
Final published version, 1.33 MBLicence: None: All rights reserved

https://ashpublications.org/bloodadvances/article/4/2/356/440609/BCLW-is-dispensable-for-the-sustained-survival-ofLicence: None: All rights reserved

Cite this

@article{e68d474ddb50456a985a21ed54178823,

title = "BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines",

abstract = "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.",

author = "Diepstraten, {Sarah T} and Catherine Chang and Lin Tai and Jia-Nan Gong and Ping Lan and Dowell, {Alexander C} and Taylor, {Graham S} and Andreas Strasser and Kelly, {Gemma L}",

note = "Funding 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology.",

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doi = "10.1182/bloodadvances.2019000541",

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AU - Diepstraten, Sarah T

AU - Chang, Catherine

AU - Tai, Lin

AU - Gong, Jia-Nan

AU - Lan, Ping

AU - Dowell, Alexander C

AU - Taylor, Graham S

AU - Strasser, Andreas

AU - Kelly, Gemma L

N1 - Funding 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. Funding Information: 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. Publisher Copyright: © 2020 by The American Society of Hematology.

PY - 2020/1/28

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N2 - 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.

AB - 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.

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BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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