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Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5
Charles W M Roberts1, Monique M Leroux, Mark D Fleming
1Division of Hematology-Oncology, Dana-Farber Cancer Institute and Children's Hospital, Department of Pediatrics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Abstract:
Recent data suggest the SWI/SNF chromatin remodeling complex may also act as a tumor suppressor. Utilizing a reversibly inactivating conditional allele, we demonstrate that loss of Snf5/Ini1/Baf47/SmarcB1, a core subunit of SWI/SNF, results in highly penetrant cancer predisposition with 100% of mice developing mature CD8(+) T cell lymphoma or rare rhabdoid tumors with a median onset of only 11 weeks. Notably, while loss of Snf5 predisposes to aggressive cancers, it is also required for survival of virtually all nonmalignant cells in vivo. Reversible gene targeting demonstrates a critical and specific role for Snf5 in tumor suppression, provides a novel system in which to explore the genetic pathways involved in tumor suppression by Swi/Snf, and should be of wide use in evaluating other essential tumor suppressor genes.
Insights
Loss of the SWI/SNF complex subunit Snf5 causes aggressive cancers in mice, yet is essential for normal cell survival. This study highlights Snf5
Area of Science:
- Cancer Biology
- Chromatin Remodeling
- Tumor Suppression
Background:
- The SWI/SNF chromatin remodeling complex is increasingly recognized for its role in tumor suppression.
- Understanding the specific functions of SWI/SNF subunits in cancer development is crucial.
Purpose of the Study:
- To investigate the tumor suppressor role of Snf5, a core SWI/SNF subunit, using a conditional knockout model.
- To establish a system for studying SWI/SNF-mediated tumor suppression and evaluating other tumor suppressor genes.
Main Methods:
- Development and utilization of a reversibly inactivating conditional allele for Snf5.
- Cancer predisposition analysis in mice with targeted Snf5 loss.
- Assessment of Snf5's requirement for nonmalignant cell survival in vivo.
Main Results:
- Loss of Snf5 leads to highly penetrant cancer predisposition, with 100% of mice developing CD8(+) T cell lymphoma or rhabdoid tumors.
- The median onset for these aggressive cancers was as early as 11 weeks.
- Snf5 is essential for the survival of virtually all nonmalignant cells, despite its role in cancer predisposition.
Conclusions:
- Snf5 plays a critical and specific role in tumor suppression.
- Reversible gene targeting of Snf5 provides a valuable system for exploring cancer genetic pathways.
- This approach can aid in evaluating the function of other essential tumor suppressor genes.