Our laboratory wishes to define, localize and study the mode of action of genes involved in susceptibility/resistance to x-irradiation-induced leukemia. We have recently identified the major locus involved in susceptibility to fractionated irradiation (FX)-induced leukemia, Ril-1. We have now detected polymorphism among congenic mouse strains differing at Ril-1 with a cloned DNA probe specific for the spleen focus forming virus (SFFV). When DNA from these congenic mice is digested with restriction enzyme PvuII, a 5.7 kb fragment is present is susceptible (C57BL/6) but not resistant (B6.C-H-30c) mice. Since these mice are identical at most genes, except Ril-1, and tightly linked genes, the PvuII fragment in question must be encoded by Ril-1 or tightly linked loci. Further studies have shown that the probable distance of the fragment from Ril-1 is 0-60 kilobases. Therefore, it now appears possible to clone Ril-1. Starting with the 5.7 kb PvuII fragments we propose to first derive a single copy probe specific for cellular sequences in the Ril-1 region, then isolate the complete gene from lambda and/or cosmid libraries. Such gene(s) will be micro-injected into embryos, and transfected into transplanted bone marrow cells in order to unequivocally demonstrate their functional role in FX-induced leukemia. In addition, experiments will be performed to try to understand the mechanism of Ril-1 action in FX-induced leukemia. These experiments will include measurement of (1) temporal changes in mRNA levels or size of transcripts, (2) rearrangements or translocation of Ril-1 DNA sequences, (3) the activation of Ril-1 on subsets of lymphocytes, and (4) the development of serological reagents for Ril-1 to aid in biochemical and cellular studies of the gene product(s).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035482-03
Application #
3173054
Study Section
Virology Study Section (VR)
Project Start
1984-03-01
Project End
1988-03-31
Budget Start
1986-03-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Pampeno, C L; Meruelo, D (1996) A novel cDNA transcript expressed in fractionated X-irradiation-induced murine thymomas. Cell Growth Differ 7:1113-23
Suzuki, H; Brown, G D; Ohno, K et al. (1996) Infection of human cells by murine ecotropic viruses: retroviral vectors carrying the hygromycin resistance-encoding gene. Gene 170:255-9
Samejima, Y; Meruelo, D (1995) 'Bystander killing' induces apoptosis and is inhibited by forskolin. Gene Ther 2:50-8
Yoshimoto, T; Yoshimoto, E; Meruelo, D (1993) Identification of amino acid residues critical for infection with ecotropic murine leukemia retrovirus. J Virol 67:1310-4
Nobunaga, T; Brown, G D; Morris, D R et al. (1992) A novel DNA binding activity is elevated in thymocytes expressing high levels of H-2Dd after radiation leukemia virus infection. J Immunol 149:871-9
Yoshimoto, T; Yoshimoto, E; Meruelo, D (1992) Enhanced gene expression of the murine ecotropic retroviral receptor and its human homolog in proliferating cells. J Virol 66:4377-81
Kamiura, S; Nolan, C M; Meruelo, D (1992) Long-range physical map of the Ly-6 complex: mapping the Ly-6 multigene family by field-inversion and two-dimensional gel electrophoresis. Genomics 12:89-105
Yoshimoto, T; Yoshimoto, E; Meruelo, D (1991) Molecular cloning and characterization of a novel human gene homologous to the murine ecotropic retroviral receptor. Virology 185:10-7
Brown, G D; Nobunaga, T; Morris, D R et al. (1991) In vivo stimulation of H-2Dd expression following RadLV infection of thymocytes: increased transcription and DNA-binding activity to sequences 5' of the Dd gene. Res Immunol 142:431-40
Brown, G D; Egan, G; Dowling, T et al. (1990) Increased H-2Dd expression following infection by a molecularly cloned ecotropic MuLV. Immunogenetics 31:94-103

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