INFECTION WITH A KIRSTEN-RETROVIRUS CAN INDUCE A MULTIPLICITY OF TUMORIGENIC PHENOTYPES IN THE INTERLEUKIN-3-DEPENDENT FDC-P1 CELLS

The identification of ras oncogenes in both human and animal tumors as well as in preleukemic and precancerous lesions suggests that activat ed ms genes participate in neoplastic development, yet the precise rol e of ras oncogenes in leukemogenesis is not clear. To assess the funct ional role of ras genes in tumorigenesis, we introduced with a retrovi ral vector either a wild-type (Gly-12) or a mutant (Val-12) Kirsten ra s cDNA into the cells of a factor-dependent myeloid cell line, FDC-P1. FDC-P1 cells are nontumorigenic and their proliferation is dependent on either interleukin-3 (IL-3) or granulocyte-macrophage colony-stimul ating factor (GM-CSF). The Ki-Val 12-infected FDC-P1 cell population i s still strictly IL-3-dependent but has acquired the ability to surviv e up to 72 hours in the absence of growth factor and to form tumors in nude mice. These tumors are easily established into cell lines that a re clonal and show a multiplicity of phenotypes with respect to their growth factor dependence. These results suggest that, in contrast with the overexpression of a normal Ki-ras, a Ki-ms oncogene can efficient ly promote the tumorigenic conversion of FDC-P1 cells. However, the cl onality of the tumors as well as the distinct phenotypes indicates tha t other genetic events are required for tumorigenicity. Therefore, in FDC-P1 cells, an activated ras gene acts as a dominant oncogene throug h the induction of tumor progression. Finally, in this simple experime ntal system we observed a multiplicity of tumorigenic phenotypes which are reminiscent of those observed in patients with acute myeloid leuk emia.