Open AccessAberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients
Author(s) -
Elias Marjanu Hikmah,
Azlan Husin,
Sulong Sarina,
Baba Abdul Aziz,
Ankathil Ravindran
Publication year - 2018
Publication title -
cancer reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.261
H-Index - 5
ISSN - 2573-8348
DOI - 10.1002/cnr2.1111
Subject(s) - imatinib mesylate , myeloid leukemia , imatinib , dna methylation , methylation , biology , cancer research , abl , leukemia , medicine , oncology , genetics , tyrosine kinase , gene , gene expression , signal transduction
Abstract Background 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 BCR‐ABL dependent and BCR‐ABL independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR‐ABL independent mechanisms are still not robustly understood. Aim To investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients. Methods and results Samples from 175 Philadelphia positive CML patients (83 good response and 92 BCR‐ABL non‐mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut‐off point followed by multiple logistic regression analysis. Log‐Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut‐off point was found to be at 62.5% for both HOXA4 and HOXA5 . Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 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 ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant ( P ‐value = 0.126 for HOXA4 ; P ‐value = 0.217 for HOXA5 ). Conclusion Hypermethylation of the HOXA4 and HOXA5 promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the BCR‐ABL gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.