Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness.
Leukemia cell infiltration and the induction of lethal hematopoietic disease in immune-deficient SCID mice transplanted with human T cell acute lymphoblastic T leukemia (T-ALL) cells occurred only when the cells possessed mutant p53 genes and lacked a wild-type allele or when T-ALL cells lacking p53 protein were infected with specific mutant p53 genes. A series of six mutant p53 genes were cloned from relapse T-ALL-derived cell lines and were constructed into defective retroviral expression vectors. Viruses encoding mutant p53 proteins were used to infect relapse T-ALL cells in a study designed to compare their pathogenic potency. The mutant p53 genes possessed a distinct hierarchy in vivo and in vitro: mutants inducing the greatest increase in proliferation of different T-ALL lines in vitro and colony formation in methylcellulose cultures also induced tissue invasiveness of infected T-ALL cells in vivo. Mutant p53 gene transfer to a cell line lacking p53 protein showed that the more potent p53 mutants possessed a distinctive dominant oncogenic activity in vitro and in vivo. The dominant oncogenic activity 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 bona fide gain-of-function mutations. Infection of p53-negative T-ALL cells with viruses encoding gain-of-function mutant p53 genes resulted in the acquisition of metastatic potential and tissue invasiveness. Taken together, our results suggest that specific mutant p53 genes play a role in the generation of lymphohematopoietic metastatic potential and tissue invasiveness as assayed in SCID mice, whereas the expression of wild-type p53 is capable of keeping this metastatic potential in check.
Hsiao
M
M
Department of Biology/Cancer Center, University of California, San Diego, La Jolla.
Low
J
J
Dorn
E
E
Ku
D
D
Pattengale
P
P
Yeargin
J
J
Haas
M
M
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002999:Clone Cells / Q000502:physiology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005822:Genetic Vectors; D006413:Hematopoietic System / Q000473:pathology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000503:physiopathology*; D008208:Lymphatic System / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000503:physiopathology; D012190:Retroviridae; D014162:Transfection; D014407:Tumor Cells, Cultured