GAIN-OF-FUNCTION MUTATIONS OF THE P53 GENE INDUCE LYMPHOHEMATOPOIETICMETASTATIC POTENTIAL AND TISSUE INVASIVENESS

Leukemia cell infiltration and the induction of lethal hematopoietic d isease in immune-deficient SCID mice transplanted with human T cell ac ute lymphoblastic T leukemia (T-ALL) cells occurred only when the cell s possessed mutant p53 genes and lacked a wild-type allele or when T-A LL cells lacking p53 protein were infected with specific mutant p53 ge nes. A series of six mutant p53 genes were cloned from relapse T-ALL-d erived cell lines and were constructed into defective retroviral expre ssion vectors. Viruses encoding mutant p53 proteins were used to infec t relapse T-ALL cells in a study designed to compare their pathogenic potency. The mutant p53 genes possessed a distinct hierarchy in vivo a nd in vitro: mutants inducing the greatest increase in proliferation o f different T-ALL lines in vitro and colony formation in methylcellulo se cultures also induced tissue invasiveness of infected T-ALL cells i n vivo. Mutant p53 gene transfer to a cell line lacking p53 protein sh owed that the more potent p53 mutants possessed a distinctive dominant oncogenic activity in vitro and in vivo. The dominant oncogenic activ ity of these mutant p53 proteins was not dependent on the presence of and on complex formation with wild-type p53 protein. These ''hot'' p53 mutations thus represent encoding gain-of-function mutations. Infecti on of p53-negative T-ALL cells with viruses encoding gain-of-function mutant p53 genes resulted in the acquisition of metastatic potential a nd tissue invasiveness. Taken together, our results suggest that speci fic mutant p53 genes play a role in the generation of lymphohematopoie tic metastatic potential and tissue invasiveness as assayed in SCID mi ce, whereas the expression of wild-type p53 is capable of keeping this metastatic potential in check.