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Using RNA interference to tune gene activity in stem cells

The application of RNA interference (RNAi) to the study of mammalian biology and disease has the potential to revolutionize biomedical research and speed the development of novel therapeutic strategies.

A series of studies by Greg Hannon at Cold Spring Harbor Laboratory (CSHL) have revealed a great deal of information about the mechanism of RNAi, as well as how RNAi can be adapted for use in medical research. These and other studies led Science to name discoveries concerning RNAi the "Breakthrough of the Year" for 2002 among all of the sciences.

Now, researchers at CSHL have shown that RNAi can be used to set the level of gene activity in stem cells on "low," "medium," or "high."

The new study indicates that stable suppression of deleterious genes by RNAi--in which adult stem cells are isolated, modified ex vivo, and then re-introduced into the affected individual--might be an effective strategy for treating human disease.

The study, published in the February issue of Nature Genetics, focussed on the role of a tumor suppressor gene called p53 in a mouse model of lymphoma.

In the mouse model, forced expression of the Myc oncogene in B-cells causes the mice to develop B-cell lymphomas by 4 to 6 months of age. The scientists, led by Greg Hannon and his CSHL colleague, Scott Lowe, knew that completely deleting the p53 gene causes lymphomas to develop much sooner, and in a more aggressive, highly-invasive form, than lymphomas that develop when the p53 gene is present.

To test the effect of decreasing p53 to particular levels via RNA interference, the scientists reconstituted the blood cells of mice by first irradiating the animals to destroy their endogenous, bone marrow supply of hematopoietic stem cells, and then injected the mice with a fresh supply of hematopoietic stem cells that had been engineered through RNAi to produce low, medium, or high levels of p53.

The study showed that establishing different l
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Contact: Peter Sherwood
sherwood@cshl.edu
516-367-6947
Cold Spring Harbor Laboratory
2-Feb-2003


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