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Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

Using gene targeting techniques, mice that have been generated with two germ-line p53 null alleles (homozygotes) develop normally but are highly susceptible to early onset spontaneous tumours. Here, we show that mice with a single null p53 allele (heterozygotes) produced in the same way are also susceptible to spontaneous tumours, but with a delayed onset compared to homozygotes. The most frequent tumour type in homozygotes was malignant lymphoma; in heterozygotes, osteosarcomas and soft tissue sarcomas predominated. Heterozygous mice treated with a liver carcinogen, dimethylnitrosamine, showed a decreased survival time in comparison to treated wild type mice, suggesting that the p53-deficient mice may be useful for some in vivo carcinogenesis assays.

Using gene targeting in embryonic stem cells, we have generated mice with one or two null p53 germ line alleles. Mice with both p53 alleles inactivated are developmentally normal but highly susceptible to the early development of spontaneous tumors. Initial studies were performed in mice with a mixed inbred genetic background (75% C57BL/6 and 25% 129/Sv) (Donehower et al., Nature (London) 356, 215-221, 1992). To study the effect of genetic background on tumorigenesis in p53-deficient mice, we have put the p53 null allele into a pure 129/Sv background and monitored tumor development. 129/Sv mice with two p53 null alleles developed tumors sooner than the mixed genetic background p53-deficient animals. The most frequently observed tumor in p53 null mice of both genetic backgrounds was a malignant lymphoma. Because the 129/Sv strain has a low incidence of lymphoma, the frequent occurrence of lymphomas in all p53 null mice suggests that this particular tumor type may be a direct result of p53 loss and not a result of a particular genetic background. In addition to malignant lymphomas, the 129/Sv p53-deficient mice showed an increased incidence of aggressive teratocarcinomas (8 of 18 tumor-bearing males), a tumor type rare in virtually all inbred mice except for 129 strains. Thus, it appears that loss of p53 may accelerate a prior tumor predisposition and that genetic background can play a role in mediating both the rate and spectrum of tumor development in these mice.

Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.