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

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

Journal article

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

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

Genes and Development | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2014

DOI: 10.1101/gad.232009.113

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 lymphom..

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University of Melbourne Researchers

Gemma Kelly Author

David Huang Author

Marco Herold Author

Andreas Strasser Author

Related Projects (1)

EVALUATION OF TUMOUR HETEROGENEITY IN THE INITIATION AND MAINTENANCE OF AML AND FOLLOWING RESPONSE TO THERAPY.

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Funding Acknowledgements

We thank G. Siciliano and his team for help with animal husbandry, C. McLean for editorial assistance, Dr. J.M. Adams and Dr. S. Cory for advice and discussions, and Dr. Kelly Rogers for help with imaging of mice. This work is supported by a Kay Kendall Leukemia Fund Intermediate Fellowship (KKL331) and an EMBO short-term fellowship (both awarded to G.L.K.); the National Health and Medical Research Council, Australia (program grant 1016701 and fellowship 1020363 to A. S., project grant APP1049720 to M.J.H., project grant APP1041936 to W.D.F., and career development fellowship APP1024620 to E.F.L.); Cancer Research UK (program grant awarded to L.F., M. Rowe, andA.B.R.); the Leukemia Foundation; the Leukemia and Lymphoma Society (specialized center of research 7001-13); and a German Research Council Fellowship (He 5740/1-1 awarded to M.J.H.). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.