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

Kelly, GL; Grabow, S; Glaser, SP; Fitzsimmons, L; Aubrey, BJ; Okamoto, T; Valente, LJ; Robati, M; Tai, L; Fairlie, WD; Lee, EF; Lindstroem, MS; Wiman, KG; Huang, DCS; Bouillet, P; Rowe, M; Rickinson, AB; Herold, MJ; Strasser, A

Author(s): Kelly, GL; Grabow, S; Glaser, SP; Fitzsimmons, L; Aubrey, BJ; Okamoto, T; Valente, LJ; Robati, M; Tai, L; Fairlie, WD; Lee, EF; Lindstroem, MS; Wiman, KG; Huang, DCS; Bouillet, P; Rowe, M; Rickinson, AB; Herold, MJ; Strasser, A;
Details: Publication Year 2014-01-01,Volume 28,Issue #1,Page 58-70
Journal Title: Genes Dev
Publication Type: Journal Article
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: cancer ; apoptosis ; MCL-1 ; p53 ; BCL-2 ; MYC
Research Division(s): Molecular Genetics Of Cancer; Cancer And Haematology; Chemical Biology; Structural Biology
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894413/
Publisher's Version: https://doi.org/10.1101/gad.232009.113
Open Access at Publisher's Site: http://genesdev.cshlp.org.ezp.lib.unimelb.edu.au/content/28/1/58.long
NHMRC Grants: NHMRC/1016701, NHMRC/1020363, NHMRC/1049720, NHMRC/1041936,
Terms of Use/Rights Notice: © 2014 Kelly et al.; Published by Cold Spring Harbor Laboratory Press 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.ezp.lib.unimelb.edu.au/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/.

Creation Date: 2014-01-14 03:36:32