Abstract

Malignant transformation is regarded as a multistage process in which genetic alterations are integral events at one or more steps in the multistage pathway leading to tumor development. N-methyl-N-nitrosourea (MNU) is a potent carcinogen that is thought to mediate its effect through alkylating DNA. A single injection of MNU induces thymic lymphoma development in several mouse strains via multiple events (hits). AKR mice are a high lymphoma incidence strain that develop spontaneous thymic lymphoma at 10-12 months of age. Fewer hits are required for MNU induced lymphoma in the AKR strain indicating that AKR mice possess a dominant gene making them more suseptible to lymphoma development. In AKR mice a genetic recombination event between endogenous murine leukemia proviral loci results in recombinant murine leukemia viruses (MLV) that are thought to be the proximal cause of disease. It has been suggested that activation and/or rearrangement of endogenous MLV proviral loci also contribute to chemically induced lymphomagenesis. However, this is a controversial issue and it is difficult to compare the mechanisms involved in chemical vs. viral induced lymphomagenesis in different mouse strains since multiple genetic loci contribute to the host's suseptibility and response to disease. This project is directed towards determining the significance of MLV related cell surface antigens and genetic rearrangements as causative factors leading to lymphomagenesis induced by MNU treatment of young AKR mice. This objective will be accomplished by investigating cellular, molecular and genetic events taht occur during MNU induced lymphomagenesis in young AKR mice. The expression of cell surface differentiation and viral antigens on preleukemic and lymphoma cells will be determined by immunofluouescence and immunochemical techniques. Genetic rearrangements of MLV related genes and selected cellular oncogenes will be evaluated using southern blotting and restriction mapping techniques on lymphoma DNA and molecular clones of endogenous MLV and associated flanking cellular sequences. Finally, isolation of cellular transforming genes from MNU vs spontaneous lymphomas will be carried out by transfection studies using either molecular clones of MLV related sequences or lymphoma DNA and sib selection procedures.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037912-03
Application #
3175861
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1984-08-01
Project End
1988-06-30
Budget Start
1987-02-01
Budget End
1988-06-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Gomez, G; Clarkin, K Z; Kraig, E et al. (2000) TCR v(beta) repertoire restriction and lack of CDR3 conservation implicate TCR-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas. Int Immunol 12:263-70
Richie, E R; Walker, D A (2000) Production and characterization of immature murine T-lymphoma cell lines. Methods Mol Biol 134:177-84
Robles, A I; Larcher, F; Whalin, R B et al. (1996) Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci U S A 93:7634-8
Richie, E R; Angel, J M; Rinchik, E M (1996) Tlag1, a novel murine tumor susceptibility gene that regulates MNU-induced thymic lymphoma development. Prog Clin Biol Res 395:23-32
Poetschke, H L; Klug, D B; Walker, D et al. (1996) Cross-linking the TCR complex induces apoptosis in CD4+8+ thymocytes in the presence of cyclosporin A. Dev Immunol 5:1-15
Romach, E; Moore, J; Rummel, S et al. (1994) Influence of sex and carcinogen treatment protocol on tumor latency and frequency of K-ras mutations in N-methyl-N-nitrosourea-induced lymphomas. Carcinogenesis 15:2275-80
Richie, E R; McEntire, B B; Coghlan, L et al. (1991) Murine T-lymphomas corresponding to the immature CD4-8+ thymocyte subset. Dev Immunol 1:255-63
Stettner, S L; Rummel, S A; Conti, C J et al. (1991) N-methyl-N-nitrosourea alters thymocyte subset distribution and targets immature CD4-8+ cells for lymphoma development. Cancer Res 51:737-40
Richie, E R; Angel, J M; Cloyd, M W (1991) Influence of murine leukemia proviral integrations on development of N-methyl-N-nitrosourea-induced thymic lymphomas in AKR mice. J Virol 65:5751-6
Nairn, R S; McIntyre, B W; Richie, E R et al. (1989) Characterization of env gene recombination in x-ray--induced thymomas of C57BL/6 mice. Mol Carcinog 2:126-30

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