Document Detail


Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach.
MedLine Citation:
PMID:  17008552     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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; Tim H Brümmendorf
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-28
Journal Detail:
Title:  Blood     Volume:  109     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-07     Completed Date:  2007-03-20     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1701-11     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Benzamides
Cell Proliferation / drug effects
Down-Regulation / genetics
Drug Delivery Systems
Drug Synergism
Fusion Proteins, bcr-abl*
Gene Expression Regulation, Leukemic*
Humans
K562 Cells
Leukemia / drug therapy*,  pathology
Lysine / analogs & derivatives*,  antagonists & inhibitors,  metabolism
Peptide Initiation Factors / genetics,  metabolism*
Piperazines / pharmacology
Protein Processing, Post-Translational
Proteomics / methods
Pyrimidines / pharmacology
RNA-Binding Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
G84/6317//Medical Research Council; SCD/04//Chief Scientist Office
Chemical
Reg. No./Substance:
0/Benzamides; 0/Peptide Initiation Factors; 0/Piperazines; 0/Pyrimidines; 0/RNA-Binding Proteins; 0/eukaryotic translation initiation factor 5A; 34994-11-1/hypusine; BKJ8M8G5HI/imatinib; EC 2.7.10.2/Fusion Proteins, bcr-abl; K3Z4F929H6/Lysine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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