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Moloney murine leukemia virus-induced tumors: recombinant proviruses in active chromatin regions
Abstract:
The DNase I sensitivity of chromosomal DNA regions carrying integrated proviral genomes of Moloney (M-MuLV) and AKR Murine Leukemia Virus (AKR-MuLV), and the cellular homologue of the mos-gene (c-mos) of Moloney Sarcoma Virus (MSV) were studied in tumor tissues of leukemic mice. The genetically transmitted sequences of M-MuLV, AKR-MuLV, and the c-mos gene are all in DNase I resistant chromatin conformations in M-MuLV-induced tumors. Each M-MuLV-induced tumor contained at least one somatically acquired integrated recombinant MuLV genome that displayed two main characteristic features of active chromatin: a) a configuration hypersensitive to DNase I, and b) extensive hypomethylation. DNase I hypersensitive sites were mapped at the junction of cellular sequences and the 5'-viral large terminal repeat (LTR). Expression of a recombinant MuLV seems therefore to be a necessary feature to maintain the transformed state.
Insights
Integrated Moloney Murine Leukemia Virus (M-MuLV) genomes in tumors show active chromatin features. Somatically acquired recombinant M-MuLV genomes are DNase I hypersensitive and hypomethylated, suggesting expression is key for maintaining the transformed state.
Area of Science:
- Virology
- Molecular Biology
- Cancer Research
Background:
- Studied DNase I sensitivity of integrated proviral genomes (Moloney Murine Leukemia Virus, AKR Murine Leukemia Virus) and c-mos gene in leukemic mouse tumors.
- Genetically transmitted sequences of M-MuLV, AKR-MuLV, and c-mos were found in DNase I resistant chromatin in M-MuLV-induced tumors.
Purpose of the Study:
- To investigate the chromatin conformation of integrated viral genomes and oncogenes in tumor tissues.
- To determine the relationship between viral genome expression and the maintenance of the transformed state.
Main Methods:
- DNase I sensitivity assays on tumor tissues from leukemic mice.
- Mapping of DNase I hypersensitive sites.
- Analysis of DNA methylation patterns.
Main Results:
- Genetically transmitted M-MuLV, AKR-MuLV, and c-mos sequences exhibit DNase I resistant chromatin.
- M-MuLV-induced tumors harbor somatically acquired recombinant MuLV genomes with DNase I hypersensitive sites and hypomethylation.
- Hypersensitive sites were localized at the junction of cellular DNA and the 5'-viral large terminal repeat (LTR).
Conclusions:
- Active chromatin features (DNase I hypersensitivity, hypomethylation) characterize somatically acquired recombinant MuLV genomes.
- Expression of recombinant MuLV is likely essential for maintaining the transformed cellular state in these tumors.