Abstract
Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis.
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 82272702
Award Identifier / Grant number: 82302925
Funding source: Natural Science Foundation of Zhejiang Province
Award Identifier / Grant number: LQ23H160012
Award Identifier / Grant number: LTGY23H080005
Award Identifier / Grant number: LZ23H160001
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: Unassigned
Funding source: Key Discipline of Zhejiang Province in Medical Technology
Award Identifier / Grant number: Unassigned
Acknowledgments
This research was supported by Zhejiang Provincial Natural Science Foundation of China (LTGY23H080005, LZ23H160001 and LQ23H160012), National Natural Science Foundation of China (82272702, 82302925), and in part supported by the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A).
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Research ethics: The in vitro isolation and purification of normal PBMC and CD34+ cells protocol was approved by the Ethics Committee of Wenzhou Medical University.
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Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: The authors state no conflict of interest.
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Research funding: This research was supported by Zhejiang Provincial Natural Science Foundation of China (LTGY23H080005, LZ23H160001 and LQ23H160012), National Natural Science Foundation of China (82272702, 82302925).
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Data availability: The raw data can be obtained on request from the corresponding author.
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Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/hsz-2023-0333).
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