Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: Pivotal role of MCL1

Jia Nan Gong, Tiffany Khong, David Segal, Yuan Yao, Chris D. Riffkin, Jean Marc Garnier, Seong Lin Khaw, Guillaume Lessene, Andrew Spencer, Marco J. Herold, Andrew W. Roberts, David C.S. Huang

Research output: Contribution to journalArticleResearchpeer-review

Abstract

New therapeutic targets are needed to address the poor prognosis of patients with highrisk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or lowpassage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.

Original languageEnglish
Pages (from-to)1834-1844
Number of pages11
JournalBlood
Volume128
Issue number14
DOIs
Publication statusPublished - 1 Jan 2016

Cite this

Gong, J. N., Khong, T., Segal, D., Yao, Y., Riffkin, C. D., Garnier, J. M., ... Huang, D. C. S. (2016). Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: Pivotal role of MCL1. Blood, 128(14), 1834-1844. https://doi.org/10.1182/blood-2016-03-704908
Gong, Jia Nan ; Khong, Tiffany ; Segal, David ; Yao, Yuan ; Riffkin, Chris D. ; Garnier, Jean Marc ; Lin Khaw, Seong ; Lessene, Guillaume ; Spencer, Andrew ; Herold, Marco J. ; Roberts, Andrew W. ; Huang, David C.S. / Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma : Pivotal role of MCL1. In: Blood. 2016 ; Vol. 128, No. 14. pp. 1834-1844.
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title = "Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: Pivotal role of MCL1",
abstract = "New therapeutic targets are needed to address the poor prognosis of patients with highrisk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or lowpassage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.",
author = "Gong, {Jia Nan} and Tiffany Khong and David Segal and Yuan Yao and Riffkin, {Chris D.} and Garnier, {Jean Marc} and {Lin Khaw}, Seong and Guillaume Lessene and Andrew Spencer and Herold, {Marco J.} and Roberts, {Andrew W.} and Huang, {David C.S.}",
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Gong, JN, Khong, T, Segal, D, Yao, Y, Riffkin, CD, Garnier, JM, Lin Khaw, S, Lessene, G, Spencer, A, Herold, MJ, Roberts, AW & Huang, DCS 2016, 'Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: Pivotal role of MCL1' Blood, vol. 128, no. 14, pp. 1834-1844. https://doi.org/10.1182/blood-2016-03-704908

Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma : Pivotal role of MCL1. / Gong, Jia Nan; Khong, Tiffany; Segal, David; Yao, Yuan; Riffkin, Chris D.; Garnier, Jean Marc; Lin Khaw, Seong; Lessene, Guillaume; Spencer, Andrew; Herold, Marco J.; Roberts, Andrew W.; Huang, David C.S.

In: Blood, Vol. 128, No. 14, 01.01.2016, p. 1834-1844.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gong, Jia Nan

AU - Khong, Tiffany

AU - Segal, David

AU - Yao, Yuan

AU - Riffkin, Chris D.

AU - Garnier, Jean Marc

AU - Lin Khaw, Seong

AU - Lessene, Guillaume

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AU - Roberts, Andrew W.

AU - Huang, David C.S.

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AB - New therapeutic targets are needed to address the poor prognosis of patients with highrisk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or lowpassage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.

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