Journal
BLOOD
Volume 128, Issue 14, Pages 1834-1844Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-03-704908
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Funding
- Australian National Health and Medical Research Council [1057742, 1016647, 1016701, 9000220]
- Cancer Council Victoria
- Leukemia and Lymphoma Society (Specialized Centers of Research) [7001-13]
- Australian Cancer Research Foundation
- Victorian State Government Operational Infrastructure Support grant
- China Scholarship Council
- National Health and Medical Research Council of Australia [1057742] Funding Source: NHMRC
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New therapeutic targets are needed to address the poor prognosis of patients with high-risk 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 low-passage 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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