title: Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach.
abstract: 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.affiliation: Department of Oncology and Haematology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Artur
authors.initials: A
authors.lastname: Gontarewicz
authors.forename: Patrick
authors.initials: P
authors.lastname: Ziegler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hartmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Kammer
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Ute
authors.initials: U
authors.lastname: Brassat
authors.forename: Martin
authors.initials: M
authors.lastname: Priemer
authors.forename: Ilona
authors.initials: I
authors.lastname: Hauber
authors.forename: Thomas
authors.initials: T
authors.lastname: Wilhelm
authors.forename: Gerold
authors.initials: G
authors.lastname: Schwarz
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000235:genetics; D016503:Drug Delivery Systems; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D011743:Pyrimidines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D008239:Lysine; D010448:Peptide Initiation Factors; D010879:Piperazines; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine