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

Gemma L Kelly, Stephanie Grabow, Stefan P Glaser, Leah Fitzsimmons, Brandon J Aubrey, Toru Okamoto, Liz J Valente, Mikara Robati, Lin Tai, W Douglas Fairlie, Erinna F Lee, Mikael S Lindstrom, Klas G Wiman, David C S Huang, Philippe Bouillet, Martin Rowe, Alan B Rickinson, Marco J Herold, Andreas Strasser

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113 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)58-70
Number of pages13
JournalGenes & Development
Issue number1
Publication statusPublished - 1 Jan 2014


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