Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
Journal Title
Blood
Publication Type
Journal Article
Abstract
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 pro-survival 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, 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 sub-set of myeloma that is highly BCLXL-dependent, and the potential for co-targeting 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.
Publisher
ASH
WEHI Research Division(s)
Cancer And Haematology; Chemical Biology; Molecular Genetics Of Cancer
PubMed ID
27465916
NHMRC Grants
NHMRC/1057742 NHMRC/1016647 NHMRC/1016701
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-08-10 04:12:53
Last Modified: 2018-07-11 09:22:23
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