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Genetic profile of insertion mutations in mouse leukemias and lymphomas
G M Hansen1, D Skapura, M J Justice
1Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030 USA.
Abstract:
Murine leukemia retroviruses (MuLVs) cause leukemia and lymphoma in susceptible strains of mice as a result of insertional mutation of cellular proto-oncogenes or tumor suppressor genes. Using a novel approach to amplify and sequence viral insertion sites, we have sequenced >200 viral insertion sites from which we identify >35 genes altered by viral insertion in four AKXD mouse strains. The class of genes most frequently altered are transcription factors, however, insertions are found near genes involved in signal transduction, cell cycle control, DNA repair, cell division, hematopoietic differentiation, and near many ESTs and novel loci. Many of these mutations identify genes that have not been implicated in cancer. By isolating nearly all the somatic viral insertion mutations contributing to disease in these strains we show that each AKXD strain displays a unique mutation profile, suggesting strain-specific susceptibility to mutations in particular genetic pathways.
Insights
Murine leukemia retroviruses cause cancer through gene mutations. Researchers identified over 35 altered genes in mice, revealing unique mutation profiles and genetic pathway susceptibilities for each strain.
Area of Science:
- Oncology
- Virology
- Genetics
Background:
- Murine leukemia retroviruses (MuLVs) are known to induce leukemia and lymphoma in mice.
- These viruses cause cancer via insertional mutagenesis, altering cellular proto-oncogenes or tumor suppressor genes.
Purpose of the Study:
- To identify genes altered by MuLV insertions in AKXD mouse strains.
- To characterize the mutation profiles associated with specific mouse strains and their susceptibility to cancer.
Main Methods:
- A novel method was employed to amplify and sequence viral insertion sites.
- Over 200 viral insertion sites were sequenced across four AKXD mouse strains.
Main Results:
- More than 35 genes were identified as being altered by viral insertion.
- Transcription factors were the most frequently altered gene class, but alterations were also found near genes involved in signal transduction, cell cycle control, DNA repair, and hematopoietic differentiation.
- Many identified mutations occurred near previously uncharacterized genes or ESTs.
Conclusions:
- Each AKXD mouse strain exhibits a distinct viral insertion mutation profile.
- These unique profiles suggest strain-specific genetic susceptibilities that contribute to disease development.