Abstract 240: Functional impact of p53 hotspot mutantions on tumor development and therapy responses in the Eµ-myc mouse lymphoma model

Abstract

Abstract The tumor suppressor p53 is mutated in the majority of human cancers, and inactivation of p53 correlates with more aggressive clinical courses and resistance to therapy. Loss of p53 may result in pleiotropic cellular effects such as cell-cycle deregulation, increased survival and aneuploidy. Utilizing the Eµ-myc transgenic mouse as a model system, we previously identified apoptosis as the prime tumor suppressor function of p53 during Myc-driven lymphoma development. However, increasing evidence supports premature senescence as another p53-dependent tumor suppressor program. When exposed to therapy, apoptosis-blocked lymphomas selected against p53, because p53 not only controls apoptosis but also senescence in response to DNA damage. Most of the naturally occurring p53 mutations are missense mutations, preferentially at some ‘hotspots’, which result in expressed mutant proteins. Moreover, different entities show distinct hotspot preferences, implying that individual p53 mutants may have different impact on p53-effector programs, or may even present with novel, oncogenic functions. Revealing the functional impact of mutant p53 on cancer cell biology and subsequent response to treatment is of great interest in the field, and numerous studies including individual mutant knock-in mouse models have been conducted. Nevertheless, no comprehensive approach to elucidate the specific role of the cancer-derived mutations in tumor formation and therapy has been undertaken yet. Our study focuses on the functions of p53 hotspot mutants in a mouse model that faithfully recapitulates human B-cell lymphomagenesis. Mutant p53 constructs were introduced into Eµ-myc transgenic hematopoietic progenitor cells to generate primary malignancies that express individual. Tumor development under different wild-type/mutant p53 combinations was compared and the resulting lymphomas were assayed with particular emphasis on apoptosis and senescence as the key tumor suppressor mechanisms. Most mutants supported rapid tumor development in the presence of wild-type p53, while only some promoted lymphoma formation in p53+/- and p53-null backgrounds. These mutants are selected for since they inhibit p53-dependent apoptosis as the main cause of accelerated lymphoma development. Interestingly, these mutants did not compromise the cellular ability to enter senescence. We found senescence driven by mutant and wild-type p53 not to be strictly dependent on the p53 downstream target p21. The precise mechanism how mutant p53 induces senescence is currently under investigation. Importantly, p53 mutant-specific alterations of pro-apoptotic, pro-senescent and metabolic p53 functions have profound implications for the outcome to cancer therapy in vitro and in vivo, as we will present at the meeting. Our goal is to develop personalized treatment strategies against tumors with defined p53 lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2011-240