Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach.
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.
Balabanov
Stefan
S
Department of Oncology and Haematology, University Hospital Eppendorf, Hamburg, Germany.
Gontarewicz
Artur
A
Ziegler
Patrick
P
Hartmann
Ulrike
U
Kammer
Winfried
W
Copland
Mhairi
M
Brassat
Ute
U
Priemer
Martin
M
Hauber
Ilona
I
Wilhelm
Thomas
T
Schwarz
Gerold
G
Kanz
Lothar
L
Bokemeyer
Carsten
C
Hauber
Joachim
J
Holyoake
Tessa L
TL
Nordheim
Alfred
A
Brümmendorf
Tim H
TH
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
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