{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:24:03Z","timestamp":1791343443282,"version":"4.3.1"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T00:00:00Z","timestamp":1433376000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2015,9]]},"abstract":"Abstract<\/jats:title>A tyrosine kinase network composed of the TAM<\/jats:styled-content> receptor AXL<\/jats:styled-content> and the cytoplasmic kinases LYN<\/jats:styled-content> and SYK<\/jats:styled-content> is involved in nilotinib\u2010resistance of chronic myeloid leukaemia (CML<\/jats:styled-content>) cells. Here, we show that the E3<\/jats:styled-content>\u2010ubiquitin ligase CBL<\/jats:styled-content> down\u2010regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL<\/jats:styled-content> in K562<\/jats:styled-content> cells increases AXL<\/jats:styled-content> and LYN<\/jats:styled-content> protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL<\/jats:styled-content> in nilotinib\u2010resistant K562<\/jats:styled-content> cells (K562<\/jats:styled-content>\u2010rn) dramatically reduces AXL<\/jats:styled-content> and LYN<\/jats:styled-content> expression and resensitizes K562<\/jats:styled-content>\u2010rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34<\/jats:styled-content>+<\/jats:sup> cells. Mechanistically, the E3<\/jats:styled-content>\u2010ligase CBL<\/jats:styled-content> counteracts AXL<\/jats:styled-content>\/SYK<\/jats:styled-content> signalling, promoting LYN<\/jats:styled-content><\/jats:italic> transcription by controlling AXL<\/jats:styled-content> protein stability. Surprisingly, the role of AXL<\/jats:styled-content> in resistance was independent of its ligand GAS6<\/jats:styled-content> binding and its TK<\/jats:styled-content> activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL<\/jats:styled-content> in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML<\/jats:styled-content> cells. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4561","type":"journal-article","created":{"date-parts":[[2015,5,12]],"date-time":"2015-05-12T10:41:15Z","timestamp":1431427275000},"page":"14-24","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["CBL<\/scp> controls a tyrosine kinase network involving AXL<\/scp>, SYK<\/scp> and LYN<\/scp> in nilotinib\u2010resistant chronic myeloid leukaemia"],"prefix":"10.1002","volume":"237","author":[{"given":"Romain","family":"Gioia","sequence":"first","affiliation":[{"name":"H\u00e9matopo\u00ef\u00e8se Leuc\u00e9mique et Cibles Th\u00e9rapeutiques INSERM U1035 Universit\u00e9 de Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Tr\u00e9goat","sequence":"additional","affiliation":[{"name":"H\u00e9matopo\u00ef\u00e8se Leuc\u00e9mique et Cibles Th\u00e9rapeutiques INSERM U1035 Universit\u00e9 de Bordeaux 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