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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 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 Citation Map 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. Related Collections Neoplasia Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 From the Hannover Medical School, Department of Hematology, Hemostaseology and Oncology, Hannover; and III Medical Clinic, University Hospital of Mannheim, University of Heidelberg, Mannheim, Germany. Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate 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-dependent but not cytokine-dependent proliferation in a dose-dependent manner. Similarly, 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 harbor significant therapeutic potential for the treatment of patients with CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Sathyanarayana, A. Dev, J. Fang, E. Houde, O. Bogacheva, O. Bogachev, M. Menon, S. Browne, A. Pradeep, C. Emerson, et al. EPO receptor circuits for primary erythroblast survival Blood, June 1, 2008; 111(11): 5390 - 5399. [Abstract] [Full Text] [PDF] C. Zhu, S. Lindsey, I. Konieczna, and E. A. Eklund Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation J. Leukoc. Biol., March 1, 2008; 83(3): 680 - 691. [Abstract] [Full Text] [PDF] H. Schepers, D. van Gosliga, A. T. J. Wierenga, B. J. L. Eggen, J. J. Schuringa, and E. Vellenga STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells Blood, October 15, 2007; 110(8): 2880 - 2888. [Abstract] [Full Text] [PDF] S. Chu, L. Li, H. Singh, and R. Bhatia BCR-Tyrosine 177 Plays an Essential Role in Ras and Akt Activation and in Human Hematopoietic Progenitor Transformation in Chronic Myelogenous Leukemia Cancer Res., July 15, 2007; 67(14): 7045 - 7053. [Abstract] [Full Text] [PDF] Y. Zhang, E. Diaz-Flores, G. Li, Z. Wang, Z. Kang, E. Haviernikova, S. Rowe, C.-K. Qu, W. Tse, K. M. Shannon, et al. Abnormal hematopoiesis in Gab2 mutant mice Blood, July 1, 2007; 110(1): 116 - 124. [Abstract] [Full Text] [PDF] S. Ni, C. Zhao, G.-S. Feng, R. F. Paulson, and P. H. Correll A Novel Stat3 Binding Motif in Gab2 Mediates Transformation of Primary Hematopoietic Cells by the Stk/Ron Receptor Tyrosine Kinase in Response to Friend Virus Infection Mol. Cell. Biol., May 15, 2007; 27(10): 3708 - 3715. [Abstract] [Full Text] [PDF] C. Voena, C. Conte, C. Ambrogio, E. Boeri Erba, F. Boccalatte, S. Mohammed, O. N. Jensen, G. Palestro, G. Inghirami, and R. Chiarle The Tyrosine Phosphatase Shp2 Interacts with NPM-ALK and Regulates Anaplastic Lymphoma Cell Growth and Migration Cancer Res., May 1, 2007; 67(9): 4278 - 4286. [Abstract] [Full Text] [PDF] R. A. Van Etten Oncogenic signaling: new insights and controversies from chronic myeloid leukemia J. Exp. Med., March 19, 2007; 204(3): 461 - 465. [Abstract] [Full Text] [PDF]

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