Deregulated c-MYC expression and p53 mutations are among the most common genetic abnormalities detected in human cancer. Mutant p53 confers a poor prognosis through both loss of wild-type p53 activity as well as various proposed gain-of-function properties. We have previously shown that MYC-driven lymphomas are exquisitely dependent on the anti-apoptotic BCL-2 protein MCL-1 for their sustained survival and growth. This dependency is reduced, but not completely ablated, by p53 mutation. We hypothesize that mutant p53 confers upon lymphoma cells a survival advantage through gain-of-function activity. We have investigated the effects of five different mutant mouse p53 proteins (V170M, I192S, G280, R246Q, R270H) on the initiation, sustained growth and chemoresistance of lymphoma.
The effect of mutant p53 on lymphoma development was examined using a hematopoietic reconstitution model. Mutant p53 proteins exhibit distinct and context-specific effects during tumorigenesis. The R246Q mutant p53 protein was most potent in accelerating lymphoma development in the context of MYC over-expression. Furthermore, the R246Q mutant p53 protein demonstrated strong selection in p53-deficient (p53-/-) hematopoietic cells during reconstitution, consistent with an advantageous gain-of-function activity in emergency hematopoiesis.
We further examined the effect of mutant p53 proteins on lymphoma cell survival in vitro. Strikingly, retroviral over-expression of mutant p53 in Eμ-Myc lymphoma-derived cell lines containing wild-type p53 impaired induction of apoptosis by Nutlin3A, an inhibitor of the E3 ligase Mdm-2, the critical negative regulator of p53, despite transcriptional induction of the p53 apoptosis effectors, Puma and Noxa. Furthermore, mutant p53 proteins also afforded protection against p53-independent cell death stimuli, such as docetaxol.
Overall, these findings are consistent with a gain-of-function oncogenic role of mutant p53 in hematopoietic cells that provides a particularly potent selective advantage in the context of MYC over-expression. Importantly, different p53 mutations exhibit different functional properties, suggesting that different p53 mutations are likely to be associated with distinct risks in human neoplastic disease.