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 language | English |
|---|---|
| Pages (from-to) | 1834-1844 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 128 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 1 Jan 2016 |
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma
T2 - Pivotal role of MCL1
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
AU - Spencer, Andrew
AU - Herold, Marco J.
AU - Roberts, Andrew W.
AU - Huang, David C.S.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85030422505&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-03-704908
DO - 10.1182/blood-2016-03-704908
M3 - Article
VL - 128
SP - 1834
EP - 1844
JO - Blood
JF - Blood
SN - 0006-4971
IS - 14
ER -