Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.

Genes Dev 2014 Jan;28(1):58-70

The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;

The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustain c-MYC-driven lymphoma growth to reveal which should be targeted for cancer therapy. Remarkably, inducible Cre-mediated deletion of even a single Mcl-1 allele substantially impaired the growth of c-MYC-driven mouse lymphomas. Mutations in p53 could diminish but not obviate the dependency of c-MYC-driven mouse lymphomas on MCL-1. Importantly, targeting of MCL-1 killed c-MYC-driven human Burkitt lymphoma cells, even those bearing mutations in p53. Given that loss of one allele of Mcl-1 is well tolerated in healthy tissues, our results suggest that therapeutic targeting of MCL-1 would be an attractive therapeutic strategy for MYC-driven cancers.

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Source
http://dx.doi.org/10.1101/gad.232009.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894413PMC
January 2014
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