MOLONEY MURINE LEUKEMIA VIRUS-INDUCED LYMPHOMAS IN P53-DEFICIENT MICE- OVERLAPPING PATHWAYS IN TUMOR-DEVELOPMENT

The effect of Moloney murine leukemia virus (MoMLV) infection was exam ined in mice lacking a functional p53 gene. Virus-infected p53(-/-) mi ce developed tumors significantly faster than uninfected p53(-/-) or v irus-infected p53(+/+) littermates. However, the degree of synergy bet ween MoMLV and the p53 null genotype was weaker than the synergy betwe en either of these and c-myc transgenes. A similar range of T-cell tum or phenotypes was represented in all p53 genotype groups, including p5 3(-/-) mice, which developed thymic lymphomas as the most common of se veral neoplastic diseases. Lack of p53 was associated with higher rate s of metastasis and the ready establishment of tumors in tissue cultur e, Loss of the wild-type allele was a common feature of tumors in p53( +/-) mice and was complete in tumor cells in vitro, but this appeared to occur by a mechanism other than proviral insertion at the wild-type allele. A lower average MoMLV proviral copy number was observed in tu mors of the p53 null and heterozygote groups, suggesting that the abse nce of a functional p53 gene reduced the number of steps required to c omplete the malignant phenotype. Mink cell focus-forming virus-like pr oviruses were detected in tumors of all infected mice but were relativ ely rare in p53 null mice. Analysis of c-myc, pim-1, and pal-1 showed that these loci were occupied by proviruses in some cases but at simil ar frequencies in p53 wild-type and null mice. In conclusion, while in activation of p53 in the germ line predisposes mice to tumors similar in phenotype to those induced by MoMLV, it appears that virus-induced tumors generally occur without p53 loss. We speculate that a bcl-2-lik e function carried or induced by MoMLV may underlie this p53-independe nt pathway.