{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T15:01:08Z","timestamp":1781276468196,"version":"3.54.1"},"reference-count":45,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170177\/H0809"],"award-info":[{"award-number":["82170177\/H0809"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670154\/H0812"],"award-info":[{"award-number":["81670154\/H0812"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M690791"],"award-info":[{"award-number":["2021M690791"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR\u2010ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)\u2010based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR\u2010ABL<jats:sup>T315I<\/jats:sup>. Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin\u2010proteasome system and possess multiple functions during cancer progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b\u2010AP15. We explored the effect of b\u2010AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b\u2010AP15 on BCR\u2010ABL<jats:sup>WT<\/jats:sup> and BCR\u2010ABL<jats:sup>T315I<\/jats:sup> CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and\/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b\u2010AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour\u2010killing activity in BCR\u2010ABL<jats:sup>WT<\/jats:sup> and BCR\u2010ABL<jats:sup>T315I<\/jats:sup> CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR\u2010ABL in CML cells expressing BCR\u2010ABL<jats:sup>WT<\/jats:sup> and BCR\u2010ABL<jats:sup>T315I<\/jats:sup>. Moreover, b\u2010AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR\u2010ABL<jats:sup>WT<\/jats:sup> and BCR\u2010ABL<jats:sup>T315I<\/jats:sup> CML cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1038","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T19:05:40Z","timestamp":1662750340000},"source":"Crossref","is-referenced-by-count":10,"title":["Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Liling","family":"Jiang","sequence":"first","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation Affiliated Cancer Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University  Guangzhou P.R. 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