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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1701-1711. Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2005-03-037648. This Article Full Text (PDF) All Versions of this Article: blood-2005-03-037648v1 109/4/1701    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 Balabanov, S. Articles by Brummendorf, T. H Search for Related Content PubMed PubMed Citation Articles by Balabanov, S. Articles by Brummendorf, T. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 22, 2005 Accepted September 22, 2006 Hypusination of eukaryotic initiation factor 5A (EIF-5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach Stefan Balabanov, Artur Gontarewicz, Patrick Ziegler, Ulrike Hartmann, Winfried Kammer, Mhairi Copland, Ute Brassat, Martin Priemer, Ilona Hauber, Thomas Wilhelm, Gerold Schwarz, Lothar Kanz, Carsten Bokemeyer, Joachim Hauber, Tessa L Holyoake, Alfred Nordheim, and Tim H Brummendorf* Department of Oncology and Haematology, University Hospital Eppendorf, Hamburg, Germany Department of Haematology, Oncology and Immunology, University Medical Center, Tubingen, Germany Institute for Cell Biology, Department of Molecular Biology, ZBiT/Proteomics, University of Tubingen, Tubingen, Germany Section of Experimental Haematology, Cancer Division, University of Glasgow, Glasgow, United Kingdom Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany * Corresponding author; email: t.bruemmendorf{at}uke.uni-hamburg.de. Inhibition of Bcr-Abl tyrosine kinase with Imatinib represents a major breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, resistance to Imatinib develops frequently, particularly in late stage disease. In order to identify new cellular Bcr-Abl downstream targets, we have analyzed differences in global protein expression in Bcr-Abl-positive K562 cells treated with or without Imatinib in vitro. Among the nineteen proteins found to be differentially expressed, we detected down-regulation of eukaryotic initiation factor 5A (eIF-5A), which is essential for cell proliferation. EIF-5A represents the only known eukaryotic protein activated by post-translational hypusination. Hypusination inhibitors (HI) alone exerted an anti-proliferative effect on Bcr-Abl positive and negative leukemia cell lines in vitro. However, the synergistic dose-effect relationship found for the combination of Imatinib and HI was restricted to Bcr-Abl-positive cells. Furthermore, this synergistic effect was confirmed by cytotoxicity assays, cell cycle analysis and CFSE-labeling of primary CD34+ CML cells. Specificity of this effect could be demonstrated by co-treatment of K562 cells with Imatinib and siRNA against eIF-5. In conclusion, using a comparative proteomics approach and further functional analysis, we have identified inhibition of eIF-5A hypusination as a promising new approach for combination therapy in Bcr-Abl positive leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Gontarewicz, S. Balabanov, G. Keller, R. Colombo, A. Graziano, E. Pesenti, D. Benten, C. Bokemeyer, W. Fiedler, J. Moll, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I Blood, April 15, 2008; 111(8): 4355 - 4364. [Abstract] [Full Text] [PDF]

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