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Biotech / Medical : RNAi -- Ignore unavailable to you. Want to Upgrade?

To: Thomas who wrote (234)	6/24/2004 2:33:51 PM
From: tuck	Read Replies (1) \| Respond to of 671

[siRNA versus hematologic malignancies -- Novartis] >>J. Clin. Invest. 113:1784-1791 (2004). Stable expression of small interfering RNA sensitizes TEL-PDGFßR to inhibition with imatinib or rapamycin Jing Chen1, Nathan R. Wall2, Kerry Kocher1, Nicole Duclos1, Doriano Fabbro3, Donna Neuberg4, James D. Griffin4, Yang Shi2 and D. Gary Gilliland1 1Howard Hughes Medical Institute, Division of Hematology, Brigham and Women’s Hospital and Harvard Medical School, 2Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA. 3Novartis Pharma AG, Basel, Switzerland. 4Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Address correspondence to: D. Gary Gilliland, Division of Hematology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 355-9092; Fax: (617) 355-9093; E-mail: ggilliland@rics.bwh.harvard.edu. Received for publication December 1, 2003, and accepted in revised form March 30, 2004. Small molecule inhibitors, such as imatinib, are effective therapies for tyrosine kinase fusions BCR-ABL–TEL-PDGFßR–mediated human leukemias, but resistance may develop. The unique fusion junctions of these molecules are attractive candidates for molecularly targeted therapeutic intervention using RNA interference (RNAi), which is mediated by small interfering RNA (siRNA). We developed a retroviral system for stable expression of siRNA directed to the unique fusion junction sequence of TEL-PDGFßR in transformed hematopoietic cells. Stable expression of the siRNA resulted in approximately 90% inhibition of TEL-PDGFßR expression and its downstream effectors, including PI3K and mammalian target of rapamycin (mTOR). Expression of TEL-PDGFßR–specific siRNA (TPsiRNA) significantly attenuated the proliferation of TEL-PDGFßR–transformed Ba/F3 cells or disease latency and penetrance in mice induced by intravenous injection of these Ba/F3 cells. Although a 90% reduction in TEL-PDGFßR expression was insufficient to induce cell death, stable siRNA expression sensitized transformed cells to the PDGFßR inhibitor imatinib or to the mTOR inhibitor rapamycin. TPsiRNA also inhibited an imatinib-resistant TEL-PDGFßR mutant, and the inhibition was enhanced by siRNA in combination with PKC412, another PDGFßR inhibitor. Although siRNA delivery in vivo is a challenging problem, stable expression of siRNA, which targets oncogenic fusion genes, may potentiate the effects of conventional therapy for hematologic malignancies. << If memory serves, Novartis is being supplied by QGENF. Cheers, Tuck