Mice carrying nonsense mutant p53 develop frequent multicentric or metastatic tumors

The TP53 tumor suppressor gene is mutated in a large fraction of human tumors. Close to 11% of TP53 mutations are nonsense mutations, causing premature termination of protein synthesis and expression of truncated inactive p53 protein. The most common TP53 nonsense mutation in human cancer is R213X. To study the impact of TP53 nonsense mutations in vivo, we generated mice harboring the Trp53 nonsense mutation R210X that corresponds to human TP53-R213X. Initially, Trp53^R210X mice appear phenotypically normal, although the proportion of female Trp53^R210X/R210X mice is dramatically reduced. Female homozygous mice are poor breeders and remain smaller and lighter than female heterozygous and wildtype littermates. Trp53^R210X/R210X mice start to show tumors at 2.5 months of age, and their maximal lifespan is 8.5 months. Trp53^R210X/+ mice present tumors from 9 months of age, and by 16.5 months of age 50% of all heterozygous mice have developed overt tumors. 71% of tumors from Trp53^R210X/+ mice show loss of heterozygosity (LOH). Homozygous mice develop hematopoietic and mesenchymal tumors, most commonly T-cell lymphoma and leiomyosarcoma, and heterozygous mice develop hematopoietic, mesenchymal, epithelial and sex cord tumors, most commonly osteosarcoma and leiomyosarcoma. The tumor phenotype is similar to that of Trp53-null and Trp53-missense knock-in mice, although the Trp53^R210X/R210X mice have a high rate of multicentric or metastatic tumors, and Trp53^R210X/+ mice have a longer overall survival than Trp53^R172H/+ missense mutant knock-in mice. Treatment of T-cell lymphoma cells from Trp53^R210X/R210X mice with aminoglycoside G418 induces expression of full-length functional p53 and apoptotic cell death. Our new unique mouse model will allow further studies of the effects of Trp53 nonsense mutation in a multi-organ system and serve as a model for the Li-Fraumeni syndrome (LFS). It will also be valuable for preclinical evaluation of novel therapeutic strategies for targeting TP53 nonsense mutations in cancer.