{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T13:25:59Z","timestamp":1782912359245,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K07145"],"award-info":[{"award-number":["20K07145"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K07168"],"award-info":[{"award-number":["20K07168"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Proliferation"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The development of BCR::ABL1 tyrosine kinase inhibitors (TKIs), such as dasatinib, has dramatically improved survival in cases of chronic myeloid leukaemia (CML). However, the development of resistance to BCR::ABL1 TKIs is a clinical problem. BCR::ABL1 TKI resistance is known to have BCR::ABL1\u2010dependent or BCR::ABL1\u2010independent mechanisms, but the mechanism of BCR::ABL1 independence is not well understood. In the present study, we investigated the mechanism of BCR::ABL1\u2010independent dasatinib resistance. The expression and activation level of genes or proteins were evaluated using array CGH, real time PCR, or western blot analysis. Gene expression was modulated using siRNA\u2010mediated knockdown. Cell survival was assessed by using trypan blue dye method. We found that dasatinib\u2010resistant K562\/DR and KU812\/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and\/or activation of MOS, TPL2 and ERK1\/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib\u2010resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non\u2010responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non\u2010responder patients compared with that in responder patients. Our results indicate that activation of ERK1\/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1\/2 inhibitors may be therapeutically useful for treating BCR::ABL1\u2010independent dasatinib\u2010resistant CML.<\/jats:p>","DOI":"10.1111\/cpr.13420","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T15:01:25Z","timestamp":1677510085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Activation of <scp>ERK1<\/scp>\/2 by <scp>MOS<\/scp> and <scp>TPL2<\/scp> leads to dasatinib resistance in chronic myeloid leukaemia cells"],"prefix":"10.1111","volume":"56","author":[{"given":"Masanobu","family":"Tsubaki","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Takeda","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuichi","family":"Koumoto","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiro","family":"Usami","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Seki","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy Kindai University School of Pharmacy  Higashi\u2010Osaka Osaka 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