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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.

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NEOPLASIA

Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL–positive leukemias identified by a proteomics approach

Stefan Balabanov1,2, Artur Gontarewicz1, Patrick Ziegler2, Ulrike Hartmann2, Winfried Kammer3, Mhairi Copland4, Ute Brassat1, Martin Priemer5, Ilona Hauber6, Thomas Wilhelm3, Gerold Schwarz5, Lothar Kanz2, Carsten Bokemeyer1, Joachim Hauber6, Tessa L. Holyoake4, Alfred Nordheim5,7, and Tim H. Brümmendorf1,2

1 Department of Oncology and Haematology, University Hospital Eppendorf, Hamburg, Germany; 2 Department of Haematology, Oncology and Immunology, University Medical Center, Tübingen, Germany; 3 Institute for Cell Biology, Department of Molecular Biology, ZBiT/Proteomics, University of Tübingen, Germany; 4 Section of Experimental Haematology, Cancer Division, University of Glasgow, Scotland; 5 Institute for Cell Biology, Department of Molecular Biology, University of Tübingen, Germany; 6 Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany; 7 Proteome Center, University of Tübingen, Germany

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. To identify new cellular BCR-ABL downstream targets, we analyzed differences in global protein expression in BCR-ABL–positive K562 cells treated with or without imatinib in vitro. Among the 19 proteins found to be differentially expressed, we detected the down-regulation of eukaryotic initiation factor 5A (eIF5A), a protein essential for cell proliferation. eIF5A represents the only known eukaryotic protein activated by posttranslational hypusination. Hypusination inhibitors (HIs) alone exerted an antiproliferative effect on BCR-ABL–positive and –negative leukemia cell lines in vitro. However, the synergistic dose-response 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 cotreatment of K562 cells with imatinib and siRNA against eIF5. In conclusion, through a comparative proteomics approach and further functional analysis, we identified the inhibition of eIF5A hypusination as a promising new approach for combination therapy in BCR-ABL–positive leukemias.


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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.
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