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

Balabanov, S. et al. (2007) Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach. Blood, 109(4), pp. 1701-1711. (doi: 10.1182/blood-2005-03-037648)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2005-03-037648

Abstract

Inhibition of BCR-ABL tyrosine kinase with imatinib represents a major breakthrough in the treatment of patients with chronic myelold leukemia (CIVIL). 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+ CIVIL 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Copland, Professor Mhairi
Authors: Balabanov, S., Gontarewicz, A., Ziegler, P., Hartmann, U., Kammer, W., Copland, M., Brassat, U., Priemer, M., Hauber, I., Wilhelm, T., Schwarz, G., Kanz, L., Bokemeyer, C., Hauber, J., Holyoake, T. L., Nordheim, A., and Brummendorf, T. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:28 September 2006
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
354131Novel drug combinations for eradication of Ph+/Bcr-Abl+ haemopoietic stem cells in chronic myeloid leukaemia (CML)Mhairi CoplandMedical Research Council (MRC)G84/6317Institute of Cancer Sciences