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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.<\/jats:p>","DOI":"10.1038\/s41419-026-08799-7","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T04:07:44Z","timestamp":1777954064000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Pellino-1 reverts the progression and tyrosine kinase inhibitor resistance in chronic myeloid leukemia"],"prefix":"10.1038","volume":"17","author":[{"given":"Qian","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangsen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoran","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingjian","family":"Zu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4438-1768","authenticated-orcid":false,"given":"Chunyan","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8522-4764","authenticated-orcid":false,"given":"Baobing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"8799_CR1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/nrc3947","volume":"15","author":"F Mertens","year":"2015","unstructured":"Mertens F, Johansson B, Fioretos T, Mitelman F. 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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.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"593"}}