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

Research output: Contribution to journalArticle

Authors

  • 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
  • Marco J Herold
  • Andreas Strasser

Colleges, School and Institutes

External organisations

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

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.

Details

Original languageEnglish
Pages (from-to)58-70
Number of pages13
JournalGenes & Development
Volume28
Issue number1
Publication statusPublished - 1 Jan 2014