{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T12:00:54Z","timestamp":1772712054543,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,3,13]],"date-time":"2015-03-13T00:00:00Z","timestamp":1426204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Scientific Research","award":["24380173"],"award-info":[{"award-number":["24380173"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although imatinib has therapeutic activity for certain subsets of patients with mastocytosis, it is not always curative. Here, molecular mechanisms that confer imatinib resistance to neoplastic mast cells were investigated using an imatinib\u2010sensitive canine neoplastic mast cell line <jats:styled-content style=\"fixed-case\">VI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content> carrying a <jats:italic><jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content><\/jats:italic> c.1523A&gt;T activating mutation. Two imatinib\u2010resistant sublines were established by culturing <jats:styled-content style=\"fixed-case\">VI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content> cells in increasing concentrations of imatinib (1\u00a0<jats:italic>\u03bc<\/jats:italic>M resistant, <jats:styled-content style=\"fixed-case\">rVI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1; 10\u00a0<jats:italic>\u03bc<\/jats:italic>M resistant, <jats:styled-content style=\"fixed-case\">rVI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>10). Both sublines had a second <jats:italic><jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content><\/jats:italic> mutation c.2443G&gt;C. Recombinant <jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content> with the second mutation was insensitive to 1\u00a0<jats:italic>\u03bc<\/jats:italic>M but sensitive to 10\u00a0<jats:italic>\u03bc<\/jats:italic>M imatinib. The effect of imatinib on the phosphorylation of <jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content> and its downstream signalling proteins was then examined using these sublines. <jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> were constitutively phosphorylated in both sublines, and their phosphorylation was suppressed by 10\u00a0<jats:italic>\u03bc<\/jats:italic>M imatinib in <jats:styled-content style=\"fixed-case\">rVI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>1 cells. However, <jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content> but not <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> phosphorylation was suppressed in <jats:styled-content style=\"fixed-case\">rVI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>10 cells. The phosphorylation of <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> in <jats:styled-content style=\"fixed-case\">rVI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>10 cells was also not diminished by the Src family kinase (<jats:styled-content style=\"fixed-case\">SFK<\/jats:styled-content>) inhibitor dasatinib. This second mutation in <jats:italic><jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content><\/jats:italic> may play an important role in imatinib resistance in neoplastic mast cells. Furthermore, <jats:styled-content style=\"fixed-case\">KIT<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">SFK<\/jats:styled-content>\u2010independent activation of <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib.<\/jats:p>","DOI":"10.1111\/ejh.12526","type":"journal-article","created":{"date-parts":[[2015,2,13]],"date-time":"2015-02-13T11:20:23Z","timestamp":1423826423000},"page":"524-531","source":"Crossref","is-referenced-by-count":13,"title":["Molecular changes associated with the development of resistance to imatinib in an imatinib\u2010sensitive canine neoplastic mast cell line carrying a <i><scp>KIT<\/scp><\/i> c.1523A&gt;T mutation"],"prefix":"10.1111","volume":"95","author":[{"given":"Masato","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiori","family":"Kuroki","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukari","family":"Moriya","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukari","family":"Kozutumi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Uehara","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichiro","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University Kyonan\u2010cho Musashino\u2010shi Tokyo Japan"},{"name":"Japan Animal Referral Medical Center Kuji Takatsu\u2010ku Kawasaki\u2010shi Kanagawa 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