Abstract
BCR-ABL1, derived from structural chromosome rearrangements, is the driver mutation in chronic myeloid leukemia (CML). Targeting BCR-ABL1 for degradation is an ideal therapeutic strategy for CML, however, the regulatory mechanisms controlling BCR-ABL1 expression in CML remained unclear. Here, we identified PELI1 as a key regulator for maintaining BCR-ABL1 in CML. BCR-ABL1 upregulates PELI1 via the STAT5/FOXP3 pathway, and the increased PELI1 then interacts with and protects BCR-ABL1 from degradation in CML cells. Concurrently, PELI1 functions as a downstream effector to promote CML cell proliferation. Notably, genetic or pharmacological inhibition of PELI1 effectively suppresses the proliferation of both tyrosine kinase inhibitors (TKIs)-sensitive and TKI-resistant CML cells, as well as Leukemia stem cells (LSCs), which consequently ameliorates the disease burden and progression of CML. Collectively, our findings demonstrated that targeting PELI1 is a promising therapeutic strategy for CML that can overcome TKI resistance and eliminates LSCs.
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Acknowledgements
We thank Akihide Yoshimi and Xiaodong He for critical reading of the manuscript. We thank Prof. Jingxuan Pan (Sun Yat-sen University) for the gift of cell lines KBM5 and KBM5-T315I, Prof. Qingsong Liu (Chinese Academy of Sciences) for the gift of the MIG-BCR-ABL1 mutation plasmids, and Prof. Zhiyong Mao (Tongji University) for the gift of the DNA damage repair reporter system. We also thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.
Funding
B.Z. discloses support for the research of this work from National Key Research and Development Program of China (2024YFC2510500), National Natural Science Foundation of China (81874294), Taishan Scholars Program of of Shandong Province in China (TSQN201812015). Y.L. discloses support for the research of this work from Natural Science Foundation of Shandong Province (ZR2024MH065). Q.Z. discloses support for the research of this work from Traditional Chinese Medicine Science and Technology Project of Shandong Province in China (Z20243107). GX, ZL, JG, ML, TZ, YX, ZYL, CL, and CJ declare no relevant funding.
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All experimental procedures were performed in accordance with the relevant guidelines and regulations. All experimental protocols involving animals were conducted in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Ethics Committee of Shandong University (#20021). The use of human specimens was approved by the Ethics Committee of Heze Municipal Hospital and Qilu Hospital of Shandong University (KYLL-2023(ZM)-576). Informed consent was acquired following the Declaration of Helsinki.
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Zhou, Q., Xu, G., Li, Z. et al. Inhibition of Pellino-1 reverts the progression and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08799-7
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DOI: https://doi.org/10.1038/s41419-026-08799-7
