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

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.

authors

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

publication date

  • 2014