Poster Presentation 25th Lorne Cancer Conference 2013

Functional interactions between p53 and anti-apoptotic Mcl-1 in sustaining the survival and growth of Myc-driven lymphoma. (#229)

Gemma L Kelly 1 , Stephanie Grabow 1 , Marco J Herold 1 , Stefan Glaser 1 , Mikara Robati 1 , Lin Tai 1 , Leah Fitzsimmons 2 , Philippe Bouillet 1 , Andreas Strasser 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  2. CRUK Institute for Cancer Studies, Birmingham University, Birmingham, West Midlands, England
Evasion from apoptosis is critical for the development and expansion of malignant tumours. This was first shown for lymphomas that were elicited by deregulated expression of the cell cycle regulator c-Myc, which is abnormally over-expressed in ~70% of human cancers. Identifying the factors critical for the sustained growth of established Myc-driven lymphomas remains an important objective. Our experiments using Eµ-myc lymphomas in which Mcl-1 could be deleted acutely by tamoxifen induced Cre activation demonstrated that sustained tumour growth is dependent on the expression of the Bcl-2 pro-survival protein Mcl-1. Remarkably, these lymphomas can only tolerate heterozygous loss of mcl-1 if they acquire a mutation in the tumour suppressor p53. It has been proposed that mutant p53 proteins can directly or indirectly control expression of genes that are critical for tumour growth. We have translated our findings from mouse studies into human Burkitt Lymphoma (BL), a malignancy that is similarly driven by c-Myc overexpression, and found that the growth of these tumours is similarly dependent on Mcl-1 or Mcl-1 in combination with Bcl-xL. Furthermore, mutations in the human p53 gene are frequently detected in BL cells. Our results suggest that the combined weak targeting of mcl-1 and mutant p53 may serve as an attractive therapeutic strategy for the treatment of Myc-driven lymphomas.