The focus of this research proposal is the mechanism of tumor induction by the v-abl oncogene. Experiments with monoclonal populations of transformed cells recovered from mice infected with helper virus-free Abelson murine leukemia virus have indicated that expression of the v-abl oncogene, though necessary, is not sufficient for tumor induction in mice. Using transformed cells recovered from such preleukemic mice and immunoglobulin gene rearrangements, the target cell for tumorigenesis will be identi- fied and the process of clonal selection during tumor progression characterized. Using self-inactivating A-MuLV variants that undergo only a single cycle of replication, the role of helper virus in mice resistant to tumorigenesis by helper virus-free A- MuLV but susceptible to tumor induction by helper virus-free A-MuLV and helper virus will be determined. Cellular genes that potentiate A-MuLV tumorigenesis and may be targets for insertional mutagenesis by helper virus will be identified, and their role in A-MuLV tumor induction examined. The activities of helper virus- free A-MuLV variants that contain substituted LTRs or partial deletions in the v-abl oncogene will be analyzed by in vitro transformation of lymphoid cells and in vivo tumorigenesis in susceptible and resistant mice. Such experiments will provide insights into the genetic basis of susceptibility to tumor formation. The consequences of v-abl oncogene expression will be analyzed in non-B cell compartments of the hematopoietic lineage in order to more precisely define its oncogenic potential. Bone marrow reconstitution experiments with cells infected with retroviral vectors encoding v-abl will provide such a system. A transformation assay using A-MuLV infection of primary fetal thymocytes will be further characterized.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Virology Study Section (EVR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Largaespada, D A; Kaehler, D A; Mishak, H et al. (1992) A retrovirus that expresses v-abl and c-myc oncogenes rapidly induces plasmacytomas. Oncogene 7:811-9
Holland, G D; Ito, K; Kaehler, D A et al. (1991) Thymic targets for Abelson murine leukemia virus are early gamma/delta T lymphocytes. Proc Natl Acad Sci U S A 88:3700-4
Holland, G D; Henkemeyer, M J; Kaehler, D A et al. (1990) Conservation of function of Drosophila melanogaster abl and murine v-abl proteins in transformation of mammalian cells. J Virol 64:2226-35
Green, P L; Kaehler, D A; Bennett, L M et al. (1989) Multiple steps are required for the induction of tumors by Abelson murine leukemia virus. J Virol 63:1989-94
Risser, R; Holland, G D (1989) Structures and activities of activated abl oncogenes. Curr Top Microbiol Immunol 147:129-53
Green, P L; Kaehler, D A; McKearn, J et al. (1988) Substitution of the LTR of Abelson murine leukemia virus does not alter the cell type of virally induced tumors. Oncogene 2:585-92
Risser, R; Green, P L (1988) Abelson virus: current status of a viral oncogene. Proc Soc Exp Biol Med 188:235-42
Green, P L; Kaehler, D A; Risser, R (1987) Cell transformation and tumor induction by Abelson murine leukemia virus in the absence of helper virus. Proc Natl Acad Sci U S A 84:5932-6
Green, P L; Kaehler, D A; Risser, R (1987) Clonal dominance and progression in Abelson murine leukemia virus lymphomagenesis. J Virol 61:2192-7
Green, P L; Holland, G D; Kaehler, D et al. (1986) Determinants of Abelson murine leukemia virus pathogenesis. Curr Top Microbiol Immunol 132:62-74

Showing the most recent 10 out of 11 publications