It is thought that neoplasms are a consequence of a series of mutations in host genes that result in loss of the normal cell function, including regulation of proliferation and cell death. Slow-transforming retroviruses e.g. Murine leukemia viruses do not carry viral oncogenes, and their capacity to induce neoplasms is baed on the ability of the retroviral DNA-intermediate, the provirus, to integrate in the host DNA, and mutate or transcriptionally activate flanking cellular sequences. Inbred mouse strains like AKR and C58 are high-ecotropic virus producing strains which harbor 2 or more genetic loci for infectious ecotropic virus in their genome and develop thymic lymphomas. On the other hand the NFS mouse which has no ecotropic viral locus in its genome has an extremely low lymphoma incidence. By introducing chromosomal loci for virus from AKR or C58 into the germline of NFS by breeding, several "v-congenic" strains were developed (see 00286-17). Mice from these families develop hematopoietic neoplasms at a high frequency (80%) typically between 8-20 months of age. Lymphoma frequency was much higher and latent periods were much shorter in virus positive mice compared to virus negative mice. About 90% of these neoplasms are of B-cell lineage and include lymphoblastic, follicular and marginal zone lymphomas. More than 700 primary tumor DNAs were analyzed by Southern blot analysis for lineage determination, identification of clonal populations by examining rearrangements of immunoglobulin heavy chain and T cell receptor _ chain genes. For precise determination of new ecotropic proviral integration, a tumor DNA was compared with tail DNA from the same mouse. Since some of the viral loci in these colonies are still unstable, germ line bands may vary from mouse to mouse due to reinsertion or excision of viral genomes. In many cases, multiple restriction endonuclease digestions of DNAs were needed for precise determination of the number of newly acquired proviruses or the absence of such integrations. All lymphomas tested contained clonal populations, the majority being monoclonal, and 87% had detectable new somatic integration of ecotropic MuLV. In tests with 5 probes, these tumors rarely exhibited rearrangement of cellular genes previously described as abnormal in T or B cell tumors. So they should provide new opportunities to study pathogenesis, particularly of B cell lineage lymphomas.