Replacement of interleukin-2 (IL-2)-generated mitogenic signals by a mink cell focus-forming (MCF) or xenotropic virus-induced IL-9-dependent autocrine loop: implications for MCF virus-induced leukemogenesis.
In earlier studies, we have shown that superinfection of an interleukin-2 (IL-2)-dependent, Moloney murine leukemia virus (MoMuLV)-induced rat T-cell lymphoma line (4437A) with mink cell focus-forming (also called polytropic) murine retroviruses induces rapid progression to IL-2-independent growth. In this report, we present evidence that the vast majority (> 90%) of the IL-2-independent lines established from polytropic or xenotropic virus-infected 4437A cells carry provirus insertions in the 3' untranslated region of the IL-9 receptor gene (Gfi-2 [for growth factor independence-2]/IL-9R). Prior to superinfection, the cells express neither IL-9 nor IL-9R. Following superinfection and provirus insertion in the Gfi-2/IL-9R locus, the cells express high levels of mRNA transcripts with a truncated 3' untranslated region which are predicted to encode the normal IL-9R protein product. The same IL-2-independent cells also express IL-9 which is induced by an insertional mutagenesis-independent mechanism. The establishment of an IL-9-dependent autocrine loop was sufficient to render the cells IL-2 independent, as suggested by the finding that 4437A cells, expressing a stably transfected Gfi-2/IL-9R construct, do not require IL-2 when maintained in IL-9-containing media. Additional experiments designed on the basis of these results showed that IL-9 gene expression is induced rapidly following the infection of 4437A cells by polytropic or xenotropic viruses and occurs in the absence of selection for IL-2-independent growth. Taken together, these data suggest that infection of 4437A cells by mink cell focus-forming or xenotropic viruses induces the expression of IL-9, which in turn rapidly selects the cells expressing the IL-9 receptor through an insertional mutagenesis-dependent mechanism. Given that both the polytropic and xenotropic viruses can induce the IL-9-dependent autocrine loop, the reduced ability of the xenotropic viruses to rapidly induce IL-2 independence in culture and tumors in animals is likely to be the result of their lower growth rates.
Flubacher
M M
MM
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Bear
S E
SE
Tsichlis
P N
PN
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*; D008099:Liver / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology; D051379:Mice; D008908:Mink Cell Focus-Inducing Viruses / Q000276:immunology*; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000276:immunology*; D011533:Proviruses / Q000276:immunology; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000502:physiology*; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D015375:Receptors, Interleukin-2