The overall objective of this proposal addresses itself to the analysis of specific gene interactions between the host and viral genomes in differentiation. Recently, we have identified and characterized a recombinant inbred (RI) mouse strain designated BXH-2, which spontaneously expresses a B-tropic MuLV throughout life and has a high incidence of myeloid leukemia. The virus is not present in the germline and is maternally transmitted. Southern analysis using a highly specific ecotropic MuLV DNA-derived probe indicated that 25 independent BXH-2 tumors contained newly acquired tumor-specific proviruses and 11 of these tumors contain only a single detectable tumor-specific provirus. The BXH-2 strain was the only BXH-strain among twelve, generated by crossing two low leukemic strains (C57BL/6J x C3H/HeJ) to have a high incidence of leukemia, thus one is presented with a disease model and eleven genotypically distinct controls. In this respect we feel that BXH-2 mice represent an important new model system for study of both host and viral factors involved in myeloid leukemogenesis. Specifically utilizing BXH-RI mice we propose to: 1. Determine the host genetic factors that may influence maternal transmission, virus expression and tumor incidence; 2. To clone recombinant DNA methodology, the representative tumor-specific proviruses detected in BXH-2 tumors and to elucidate their biochemical and biological function(s); we will also clone the host DNA fragments containing integrated viral DNA sequences and determine if these sequences are integrated in a chromosomal domain, are transcribed in tumor tissues, and homologous to any previously identified viral oncogenes. 3. To determine if the BXH-2 B-ecotropic virus which induces myeloid leukemias in vivo can induce the transformation of hematopoietic cells in vitro.
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