Formation of an Active Form of the Interleukin‐2/15 Receptor Β‐chain by Insertion of the Intracisternal A Particle in a Radiation‐induced Mouse Thymic Lymphoma and Its Role in Tumorigenesis

Although many reports suggest that aberrant regulation of cytokine signaling pathways via the interleukin‐2 receptor (IL‐2R) induces tumorigenic transformation, constitutively active IL‐2R in tumors has not been reported. We searched for genomic alteration of the IL‐2/15R β‐subunit gene (IL‐2/15Rβ) in cytokine‐independent cell lines established from radiation‐induced mouse thymic lymphomas. In the TL34 cell line and its primary tumor, one of the IL‐2/15Rβ alleles was rearranged by the insertion of an intracisternal A particle (IAP) retrotransposon. The IAP‐IL2/15Rβ chimeric gene expressed chimeric mRNA in which IAP‐coding Gag‐Pol mRNA was fused to IL‐2/15Rβ mRNA and coded for Gag‐Pol‐IL‐2/15Rβ chimeric protein. Forced expression of the Gag‐Pol‐IL‐2/15Rβ chimeric cDNA in a mouse cytotoxic T‐cell line (CTLL‐2) converted IL‐2‐dependent cell growth to IL‐2‐independent growth, suggesting that the chimeric protein activates some of the IL‐2 signaling pathways necessary for cell proliferation. Downregulation of the expression of the Gag‐Pol‐IL‐2/15Rβ chimeric protein in TL34 by antisense RNA inhibited cell growth, and concomitantly reduced the level of c‐myc protein. These results suggest that the Gag‐Pol‐IL‐2/15Rβ is a constitutively active form that transmits proliferative signals by expressing downstream target genes, including c‐myc. Thus, we demonstrated that the chimeric receptor gene produced by the insertion of an IAP functions as an oncogene by providing IL‐2‐independent autonomous growth potential. © 2003 Wiley‐Liss, Inc.