{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:56:28Z","timestamp":1790963788715,"version":"4.1.0"},"reference-count":63,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,11]],"date-time":"2019-03-11T00:00:00Z","timestamp":1552262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1\/2, Akt, MEK1\/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML.<\/jats:p>","DOI":"10.3390\/ijms20051230","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T03:49:31Z","timestamp":1552362571000},"page":"1230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations\u2014Possible Therapeutic Efficacy of Cabozantinib"],"prefix":"10.3390","volume":"20","author":[{"given":"Ya-Chen","family":"Ko","sequence":"first","affiliation":[{"name":"Department of Medical Imaging and Radiological Technology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Yi","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"},{"name":"Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Hau","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwei-Fang","family":"Tien","sequence":"additional","affiliation":[{"name":"Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Liang","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiung-Fei","family":"Chien","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan"},{"name":"TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3561-1093","authenticated-orcid":false,"given":"Liang-In","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"},{"name":"Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1182\/bloodadvances.2017009829","article-title":"The role of targeted therapy in the management of patients with AML","volume":"1","author":"Perl","year":"2017","journal-title":"Blood Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1080\/1042819032000159861","article-title":"Problems related to resistance to cytarabine in acute myeloid leukemia","volume":"45","author":"Cros","year":"2004","journal-title":"Leuk. 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