Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia
Abstract BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-04153-7 |
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| author | Congyi Zhang Yikai Yao Qiuting Qian Xiongyu Han Yunkun Lu Xinyi Jiang Hongqiang Cheng Xue Zhang Ying Chi Yuehai Ke Peng Xiao |
| author_facet | Congyi Zhang Yikai Yao Qiuting Qian Xiongyu Han Yunkun Lu Xinyi Jiang Hongqiang Cheng Xue Zhang Ying Chi Yuehai Ke Peng Xiao |
| author_sort | Congyi Zhang |
| collection | DOAJ |
| description | Abstract BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML. |
| format | Article |
| id | doaj-art-4bbac47e00b84809a6b736085b9dd500 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-4bbac47e00b84809a6b736085b9dd5002025-08-20T02:03:31ZengNature PortfolioScientific Reports2045-23222025-05-0115111010.1038/s41598-025-04153-7Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemiaCongyi Zhang0Yikai Yao1Qiuting Qian2Xiongyu Han3Yunkun Lu4Xinyi Jiang5Hongqiang Cheng6Xue Zhang7Ying Chi8Yuehai Ke9Peng Xiao10Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineZhejiang University-University of Edinburgh Joint Institute, ZJU Haining International CampusZhejiang University-University of Edinburgh Joint Institute, ZJU Haining International CampusSir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineZhejiang University-University of Edinburgh Joint Institute, ZJU Haining International CampusDepartment of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of MedicineSir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML.https://doi.org/10.1038/s41598-025-04153-7Chronic myeloid leukemiaTyrosine kinase inhibitorNeddylationPost-translational modificationResistance |
| spellingShingle | Congyi Zhang Yikai Yao Qiuting Qian Xiongyu Han Yunkun Lu Xinyi Jiang Hongqiang Cheng Xue Zhang Ying Chi Yuehai Ke Peng Xiao Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia Scientific Reports Chronic myeloid leukemia Tyrosine kinase inhibitor Neddylation Post-translational modification Resistance |
| title | Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| title_full | Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| title_fullStr | Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| title_full_unstemmed | Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| title_short | Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| title_sort | neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia |
| topic | Chronic myeloid leukemia Tyrosine kinase inhibitor Neddylation Post-translational modification Resistance |
| url | https://doi.org/10.1038/s41598-025-04153-7 |
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