{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T23:54:25Z","timestamp":1783814065709,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T00:00:00Z","timestamp":1532649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Universiti Sains Malaysia, Malaysia, Research University (RU)","award":["1001\/PPSP\/812070"],"award-info":[{"award-number":["1001\/PPSP\/812070"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Imatinib mesylate is a molecularly targeted tyrosine kinase inhibitor drug. It is effectively used in the treatment of chronic myeloid leukemia (CML) patients. However, development of resistance to imatinib mesylate as a result of <jats:italic>BCR\u2010ABL<\/jats:italic> dependent and <jats:italic>BCR\u2010ABL<\/jats:italic> independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR\u2010ABL independent mechanisms are still not robustly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To investigate the correlation of <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic> promoter DNA hypermethylation with imatinib resistance among CML patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Samples from 175 Philadelphia positive CML patients (83 good response and 92 <jats:italic>BCR\u2010ABL<\/jats:italic> non\u2010mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic> promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut\u2010off point followed by multiple logistic regression analysis. Log\u2010Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut\u2010off point was found to be at 62.5% for both <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic>. Chronic myeloid leukemia patients with \u226563% <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic> methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have \u226462% and\u00a0\u2265\u00a063% methylation levels of <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic> genes were found to be not significant (<jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.126 for <jats:italic>HOXA4<\/jats:italic>; <jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.217 for <jats:italic>HOXA5<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hypermethylation of the <jats:italic>HOXA4<\/jats:italic> and <jats:italic>HOXA5<\/jats:italic> promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the <jats:italic>BCR\u2010ABL<\/jats:italic> gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cnr2.1111","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T08:55:00Z","timestamp":1532681700000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Aberrant DNA methylation at <i>HOXA4<\/i> and <i>HOXA5<\/i> genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients"],"prefix":"10.1002","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-7954","authenticated-orcid":false,"given":"Marjanu Hikmah","family":"Elias","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health Sciences Universiti Sains Islam Malaysia  Nilai Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husin","family":"Azlan","sequence":"additional","affiliation":[{"name":"Haemato\u2010Oncology Unit, Department of Internal Medicine Universiti Sains Malaysia Hospital  Kota 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