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Growing evidence suggests that ubiquitin-specific proteases (USPs) play a role in cancer treatment. Dysregulation of miR-146a has been found in both adult and pediatric patients with acute leukemia. Knockdown of glutaminase-1 (GLS1) resulted in inhibition of tumor growth. However, the role of miR-146a-5p\/USP6\/GLS1 in leukemia and chemoresistance of leukemia cells remains to be elucidated. In the current study, USP6 level was increased in bone marrow aspiration specimens of patients with CML and associated with poor prognosis. USP6 was significantly upregulated in imatinib (IM)-resistant clinical samples compared with IM-sensitive samples. USP6 overexpression significantly inhibited IM-induced apoptosis of leukemia cells. Overexpressing USP6 significantly increased GLS1 ubiquitination to decrease GLS protein. A mechanism study indicated that USP6 regulation of IM resistance of CML cells was GLS1 dependent and regulated by miR-146a-5p. Administration of human umbilical cord mesenchymal stem cell (hucMSC) exosomes promoted IM-induced cell apoptosis through miR-145a-5p\/USP6. Therefore, hucMSC exosomes promoted IM-induced apoptosis of K562-R cells by suppressing GLS1 ubiquitination to increase GLS protein via miR-146a-5p and its target GLS1. The findings highlight the importance of miR-146a-5p\/USP6\/GLS1 signaling in chemoresistance of leukemia and provide new insights into therapeutic strategies for chemoresistant leukemia.<\/jats:p>","DOI":"10.1038\/s41419-022-04531-3","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T08:03:48Z","timestamp":1643357028000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p\/USP6\/GLS1 axis"],"prefix":"10.1038","volume":"13","author":[{"given":"Xiaowen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9154-9282","authenticated-orcid":false,"given":"Hui","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huirong","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanli","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-2685","authenticated-orcid":false,"given":"Sixi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-633X","authenticated-orcid":false,"given":"Feiqiu","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"4531_CR1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ajh.25792","volume":"95","author":"E Jabbour","year":"2020","unstructured":"Jabbour E, Kantarjian H. 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