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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031102-09
Application #
3169476
Study Section
Experimental Virology Study Section (EVR)
Project Start
1981-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1991-06-30
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Cho, B C; Shaughnessy Jr, J D; Largaespada, D A et al. (1995) Frequent disruption of the Nf1 gene by a novel murine AIDS virus-related provirus in BXH-2 murine myeloid lymphomas. J Virol 69:7138-46
Bedigian, H G; Shepel, L A; Hoppe, P C (1993) Transplacental transmission of a leukemogenic murine leukemia virus. J Virol 67:6105-9
Sundberg, J P; Hanson, C A; Roop, D R et al. (1991) Myoepitheliomas in inbred laboratory mice. Vet Pathol 28:313-23
Hurbain-Kosmath, I; Berault, A; Noel, N et al. (1990) Gonadotropes in a novel rat pituitary tumor cell line, RC-4B/C. Establishment and partial characterization of the cell line. In Vitro Cell Dev Biol 26:431-40
Sundberg, J P; Burnstein, T; Shultz, L D et al. (1989) Identification of Pneumocystis carinii in immunodeficient mice. Lab Anim Sci 39:213-8
Davidson, W F; Dumont, F J; Bedigian, H G et al. (1986) Phenotypic, functional, and molecular genetic comparisons of the abnormal lymphoid cells of C3H-lpr/lpr and C3H-gld/gld mice. J Immunol 136:4075-84