Recently, we have identified and characterized a recombinant inbred (RI) mouse strain designated BXH-2, that 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 92 independent BXH-2 tumors contained newly acquired tumor- specific proviruses and 25 of these tumors contain only a single detectable tumor-specific provirus. We have molecularly cloned a B-ecotropic BXH-2 tumor specific provirus along with flanking cellular sequences. In addition there appears to be a new common site of virus integration in BXH-2 myeloid tumors that may represent a new cellular proto-oncogene involved in myeloid disease. The BXH-2 strains 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; this presents us with a disease model and eleven genotypically distinct controls. 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 use single gene mutations, some of which have an effect on myelopoiesis, to investigate how specific cell subsets interact with exogenous leukemogenic B-ecotropic MuLV in the development of myeloid leukemia; (3) to determine the time of virus infection (pre or postimplantation) of BXH-2 embryos and to derive ecotropic virus free BXH-2 mice for viral transmission and leukemogenesis studies; (4) to construct recombinant proviruses to determine which sequences within the B-ecotropic proviral genome are determinants for efficient embryo transfer of the virus for myeloid leukemia induction.
