Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach.
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Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach. / Balabanov, Stefan; Gontarewicz, Artur; Ziegler, Patrick; Hartmann, Ulrike; Kammer, Winfried; Copland, Mhairi; Brassat, Ute; Priemer, Martin; Hauber, Ilona; Wilhelm, Thomas; Schwarz, Gerold; Kanz, Lothar; Bokemeyer, Carsten; Hauber, Joachim; Holyoake, Tessa L; Nordheim, Alfred; Brümmendorf, Tim H.
in: BLOOD, Jahrgang 109, Nr. 4, 4, 2007, S. 1701-1711.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach.
AU - Balabanov, Stefan
AU - Gontarewicz, Artur
AU - Ziegler, Patrick
AU - Hartmann, Ulrike
AU - Kammer, Winfried
AU - Copland, Mhairi
AU - Brassat, Ute
AU - Priemer, Martin
AU - Hauber, Ilona
AU - Wilhelm, Thomas
AU - Schwarz, Gerold
AU - Kanz, Lothar
AU - Bokemeyer, Carsten
AU - Hauber, Joachim
AU - Holyoake, Tessa L
AU - Nordheim, Alfred
AU - Brümmendorf, Tim H
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 109
SP - 1701
EP - 1711
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 4
M1 - 4
ER -