We seek to identify the viral and host genes that govern the target cell specificity and host susceptibility to tumor induction by Abelson murine leukemia virus. To identify the viral genes that govern target cell phenotype we will construct recombinant genomes carrying A-MuLV sequences and the LTR sequences of Friend MuLV, an erythroleukemogenic virus; MCF 247, a thymotropic, lymphomagenic MCF MuLV; and AKV, a non-lymphomagenic, ecotropic MuLV. Viruses will be recovered and tested for their activity in appropriate mice. To identify host genes that govern tissue specificity we will exploit our recent observation that C57BL/6 (B6) mice rapidly developed thymomas when injected intrathymically with A-MuLV, whereas BALB/c mice developed non-thymic pre-B cell lymphomas when infected intrathymically. The disease patterns of recombinant inbred strains made between BALB/c and B6 will be investigated, and the resulting tumor phenotypes determined using serological markers and molecular probes to the T-cell receptor and immunoglobulin loci. We will also attempt to develop an in vitro thymocyte transformation assay. Examination of the DNA of 15 primary non-thymic lymphomas induced by A-MuLV indicated that a major proportion of the tumor cell population derived from very few initially infected cells because simple patterns of provirus intergration were found. We seek to determine the mechanism of this clonal dominance by determining the efficiency of in vivo infection at times after infection, and by determining if multiple independently infected clones of transformed cells exist prior to tumor emergence. Secondary events that might provide selective advantages to A-MuLV transformed cells will be investigated by examination of the expression of known cellular oncogenes in primary A-MuLV tumors cells. Non-v-abl transforming genes found in the DNA of A-MuLV lines and primary tumors will be molecularly cloned and analyzed. The activity of these genes and A-MuLV will be investigated in non-tumorigenic, IL-3 dependent, pre-B cell clones.
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