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

• Published in: Blood Vol. 109; no. 4; pp. 1701 - 1711
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.02.2007; The Americain Society of Hematology
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Benzamides; Biological and medical sciences; Cell Proliferation - drug effects; Down-Regulation - genetics; Drug Delivery Systems; Drug Synergism; Eukaryotic Translation Initiation Factor 5A; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; K562 Cells; Leukemia - drug therapy; Leukemia - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lysine - analogs & derivatives; Lysine - antagonists & inhibitors; Lysine - metabolism; Medical sciences; Peptide Initiation Factors - genetics; Peptide Initiation Factors - metabolism; Piperazines - pharmacology; Protein Processing, Post-Translational; Proteomics - methods; Pyrimidines - pharmacology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Chromosomal aberration; Imatinib; Targeted therapy; Leukemia; Initiation factor eIF5; Malignant hemopathy; Proliferation; In vitro; Synergism; Posttranslational modification; Signal transduction; Bcr-abl protein; Cell cycle; Proteomics; Abnormal chromosome; Fusion protein; Hybrid gene; Hypusin
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-03-037648

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.