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 activated ras genes participate in neoplastic development, yet the precise role of ras oncogenes in leukemogenesis is not clear. To assess the functional role of ras genes in tumorigenesis, we introduced with a retroviral vector either a wild-type (Gly-12) or a mutant (Val-12) Kirsten ras 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-stimulating factor (GM-CSF). The Ki-Val 12-infected FDC-P1 cell population is still strictly IL-3-dependent but has acquired the ability to survive 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 are 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, Ki-ras oncogene can efficiently promote the tumorigenic conversion of FDC-P1 cells. However, the clonality of the tumors as well as the distinct phenotypes indicates that other genetic events are required for tumorigenicity. Therefore, in FDC-P1 cells, an activated ras gene acts as a dominant oncogene through the induction of tumor progression. Finally, in this simple experimental system we observed a multiplicity of tumorigenic phenotypes which are reminiscent of those observed in patients with acute myeloid leukemia.
Duménil
D
D
Hématopoïèse et Cellules Souches, U. 362 INSERM, Villejuif, France.
Neel
H
H
Lacout
C
C
Dautry
F
F
D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000235:genetics; D007377:Interleukin-3 / Q000032:analysis / Q000235:genetics / Q000494:pharmacology*; D007708:Kirsten murine sarcoma virus; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D012192:Retroviridae Infections / Q000473:pathology*; D012513:Sarcoma, Experimental / Q000473:pathology*; D014412:Tumor Virus Infections / Q000473:pathology*
D007377:Interleukin-3; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor