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 interleuki n-2 (IL-2)-dependent, Moloney murine leukemia virus (MoMuLV)-induced r at T-cell lymphoma line (4437A) with mink cell focus-forming (also cal led polytropic) murine retroviruses induces rapid progression to IL-2- independent grow th. In this report, we present evidence that the vast majority (>90%) of the IL-2-independent lines established from polytr opic or xenotropic virus-infected 4437A cells carry provirus insertion s in the 3' untranslated region of the IL-9 receptor gene (Gfi-2[for g rowth factor independence-2]/IL-9R). Prior to superinfection, the cell s express neither IL-9 nor IL-9R. Following superinfection and proviru s insertion in the Gfi-2/IL-9R locus, the cells express high levels of mRNA transcripts with a truncated 3' untranslated region which are pr edicted to encode the normal IL-9R protein product. The same IL-2-inde pendent cells also express IL-9 which is induced by an insertional mut agenesis-independent mechanism. The establishment of an IL-9-dependent autocrine loop was sufficient to render the cells IL-2 independent, a s suggested by the finding that 4437A cells, expressing a stably trans fected Gfi-2/IL-9R construct, do not require IL-2 when maintained in I L-9-containing media. Additional experiments designed on the basis of these results showed that IL-9 gene expression is induced rapidly foll owing the infection of 4437A cells by polytropic or xenotropic viruses and occurs in the absence of selection for IL-2-independent growth. T aken together, these data suggest that infection of 4437A cells by min k cell focus-forming or xenotropic viruses induces the expression of I L-9, which in turn rapidly selects the cells expressing the IL-9 recep tor through an insertional mutagenesis-dependent mechanism. Given that both the polytropic and xenotropic viruses can induce the IL-9-depend ent autocrine loop, the reduced ability of the xenotropic viruses to r apidly induce IL-2 independence in culture and tumors in animals is li kely to be the result of their lower growth rates.