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.

Abstract

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.

• Authors: M M Flubacher, S E Bear, P N Tsichlis
• Journal: Journal of virology (J Virol) Vol. 68 Issue 12 Pg. 7709-16 (Dec 1994) ISSN: 0022-538X [Print] United States
• PMID: 7966560 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-2
• Receptors, Interleukin-2

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Cell Line
• Gene Expression
• Humans
• Interleukin-2 (biosynthesis, pharmacology, physiology)
• Liver (immunology)
• Lymphoma, T-Cell (immunology)
• Mice
• Mink Cell Focus-Inducing Viruses (immunology)
• Molecular Sequence Data
• Moloney murine leukemia virus (immunology)
• Proviruses (immunology)
• Rats
• Receptors, Interleukin-2 (biosynthesis, physiology)
• Restriction Mapping
• Sequence Homology, Amino Acid
• Signal Transduction
• Spleen (immunology)
• Thymus Gland (immunology)
• Transfection
• Tumor Cells, Cultured