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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3279-3287. Prepublished online as a Blood First Edition Paper on November 8, 2005; DOI 10.1182/blood-2005-08-3087. This Article Full Text (PDF) All Versions of this Article: 2005-08-3087v1 107/8/3279    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Scherr, M. Articles by Eder, M. Search for Related Content PubMed PubMed Citation Articles by Scherr, M. Articles by Eder, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 3, 2005 Accepted October 26, 2005 Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML) Michaela Scherr, Anuhar Chaturvedi, Karin Battmer, Iris Dallmann, Beate Schultheis, Arnold Ganser, and Matthias Eder* Department of Hematology,Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany Med. Clinic III, University Hospital of Mannheim, University of Heidelberg, Mannheim, Germany * Corresponding author; email: eder.matthias{at}mh-hannover.de. Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate (STI571) has rapidly become first line therapy in chronic myeloid leukemia (CML), drug resistance suggests that combination therapy directed to a complementing target may significantly improve treatment results. To identify such potential targets, we used lentivirus-mediated RNA interference (RNAi) as a tool for functional genomics in cell lines as well as primary normal and CML CD34+ cells. In a conditional cell culture model, we demonstrate that RNAi mediated reduction of SHP2, STAT5, and Gab2 protein expression inhibits Bcr-Abl- but not cytokine-dependent proliferation in a dose dependent manner. Similarily, colony formation of purified primary CML- but not of normal CD34+ colony-forming cells is specifically reduced by inhibition of SHP2, STAT5, and Gab2 expression, respectively. In addition, coexpression of both anti-Bcr-Abl and anti-SHP2 shRNAs from a single lentiviral vector induces stronger inhibition of colony formation as compared to either shRNA alone. The data indicate that Bcr-Abl expression may affect the function of normal signaling molecules. Targeting these molecules may harbour significant therapeutic potential for the treatment of CML. 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