The carcinogen N-methyl-N-nitrosourea (MNU) induces thymic lymphoma development in various inbred mouse strains. The AKR strain is particularly susceptible, experiencing a higher incidence and shorter latency (2-3 months) for MNU-induced lymphoma development than other inbred mouse strains. The molecular basis for the enhanced susceptibility of the AKR strain is not clear. However, in contrast to most inbred strains, untreated AKR mice develop spontaneous thymic lymphoma after 8 months of age due to the generation of recombinant oncogenic murine leukemia viruses (MuLV). Several reports implicate endogenous MuLV as co-factors in chemical carcinogenesis. Therefore, I have proposed that the enhanced susceptibility of AKR mice to MNU-induced lymphomagenesis involves participation of endogenous MuLV in the multistage pathway resulting in neoplastic transformation. Recently, we found aberrant expression of functional interleukin-2 receptors (IL-2Rs) on MNU-induced lymphomas. This is interesting since these tumors correspond to immature T-cells that normally down-regulate IL-2R expression. Furthermore, preliminary data suggest that IL-2Rs on MNU-induced lymphomas are associated with the MuLV envelop glycoprotein, gp70. Similar observations have been made in Friend MuLV induced erythroleukemia in which binding of a defective MuLV envelop protein gp55 to erythropoietin receptors in immature erythroblasts induces prolonged proliferation of the preneoplastic target population. In view of this precedent and preliminary data from our lab, I am proposing that NM activates expression of endogenous MuLV gp70 which can bind to and stimulate lL-2Rs on initiated thymocytes. This event is likely to trigger accelerated expansion and progression of the target population explaining, in part, the predisposition of the AKR strain to develop a high incidence of early appearing MNU-induced lymphomas.
The specific aims for this proposal are: (1). To characterize the IL-2Rs expressed on MNU-induced lymphomas with respect to number, affinity, polypeptide chain structure and functional activity. (2.) To assess IL-2R protein and mRNA expression in specific thymocyte subsets at various intervals after MNU treatment and isolate IL-2R bearing cells for analysis of clonality and oncogene activation. (3.) To determine if there is a specific cell surface and/or intracellular association between IL-2Rs and MuLV gp70 molecules in MNU-induced lymphomas as well as in thymocyte subsets obtained at intervals after MNU treatment. (4.) To identify, using a panel of monoclonal antibodies, the class(es) of endogenous MuLV gp70 molecules expressed on lymphomas and preneoplastic thymocytes as a consequence of MNU activation and to isolate relevant gp70 molecules for analysis of IL-2R binding and stimulation. (5.) To molecularly clone endogenous MuLV sequences that encode the gp70 subclass defined by specific aim #4 and develop constructs for future retroviral mediated gene transfer.
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