Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53
- Gemma L. Kelly1,2,3,7,
- Stephanie Grabow1,3,
- Stefan P. Glaser1,3,
- Leah Fitzsimmons2,
- Brandon J. Aubrey1,3,
- Toru Okamoto1,3,6,
- Liz J. Valente1,3,
- Mikara Robati1,
- Lin Tai1,
- W. Douglas Fairlie1,3,
- Erinna F. Lee1,3,
- Mikael S. Lindstrom4,
- Klas G. Wiman4,
- David C.S. Huang1,3,
- Philippe Bouillet1,3,
- Martin Rowe2,
- Alan B. Rickinson2,
- Marco J. Herold1,3,5 and
- Andreas Strasser1,3,5,7
- 1The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;
- 2School of Cancer Sciences, University of Birmingham College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
- 3Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050 Australia;
- 4Department of Oncology–Pathology, Karolinska Institute, Cancer Center Karolinska (CCK), SE-171 76 Stockholm, Sweden
-
↵5 These authors contributed equally to this work.
Abstract
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.
Keywords
Footnotes
-
↵7 Corresponding authors
E-mail strasser{at}wehi.edu.au
E-mail gkelly{at}wehi.edu.au
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.232009.113.
- Received October 1, 2013.
- Accepted November 19, 2013.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.