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Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias
Stefan Balabanov1, Artur Gontarewicz, Patrick Ziegler
1Department of Oncology and Haematology, University Hospital Eppendorf, Hamburg, Germany.
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.
Insights
Targeting eukaryotic initiation factor 5A (eIF5A) hypusination with inhibitors offers a novel combination therapy for chronic myeloid leukemia (CML). This approach synergizes with imatinib, overcoming resistance in BCR-ABL-positive leukemia cells.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Imatinib is a breakthrough therapy for chronic myeloid leukemia (CML) by inhibiting BCR-ABL tyrosine kinase.
- Resistance to imatinib is a significant clinical challenge, especially in advanced CML.
- Identifying new cellular targets is crucial for overcoming imatinib resistance.
Purpose of the Study:
- To identify novel downstream targets of BCR-ABL signaling.
- To investigate the therapeutic potential of targeting eukaryotic initiation factor 5A (eIF5A) in CML.
- To evaluate the synergistic effect of combining imatinib with hypusination inhibitors (HIs).
Main Methods:
- Comparative proteomics analysis of BCR-ABL-positive K562 cells treated with imatinib.
- Assessment of antiproliferative and cytotoxic effects of HIs alone and in combination with imatinib.
- Functional validation using cell-cycle analysis, CFSE labeling of primary CML cells, and siRNA knockdown of eIF5A.
Main Results:
- Down-regulation of eIF5A, essential for cell proliferation, was observed in imatinib-treated cells.
- Hypusination inhibitors (HIs) demonstrated antiproliferative effects on leukemia cell lines.
- A synergistic therapeutic effect was observed when combining imatinib with HIs specifically in BCR-ABL-positive CML cells and primary cells.
Conclusions:
- Inhibition of eIF5A hypusination is a promising strategy for CML treatment.
- Combining imatinib with hypusination inhibitors represents a novel and effective combination therapy for BCR-ABL-positive leukemias.
- This approach may overcome imatinib resistance and improve patient outcomes.
