TY - JOUR
T1 - Identification of DNA methylation biomarkers in imatinib-resistant chronic myeloid leukemia cells
AU - You, Ren In
AU - Ho, Ching Liang
AU - Hung, Hsiu Man
AU - Hsieh, Yu Fung
AU - Ju, Jy Ciou
AU - Chao, Tsu Yi
N1 - Funding Information:
This work was supported by a grant from the Tri-Service General Hospital ( TSGH-C99-046 ). We also thank Dr. Anthony J. Janckila from Department of Veteran's Affairs Medical Center and University of Louisville School of Medicine for providing a critical review of this article.
PY - 2012/3
Y1 - 2012/3
N2 - Drug resistance is an obstacle to successful cancer treatment. In hematological neoplasms, such as chronic myelogenous leukemia (CML), drug resistance is often associated with gene hypermethylation and loss of function. An imatinib-resistant subclone of CML-like K562 (K562-R) was used as a model to study the role of hypermethylation in drug resistance. K562-R was selected by culturing cells with increasing concentrations of imatinib, ranging from 0.2-5 μM. A DNA methylation microarray was performed on the K562-R and parental K562 cells, and selected gene expression levels were confirmed using real-time polymerase chain reaction. The methylation level was significantly increased and the gene expression level significantly was decreased for MLH1, RPRM, FEM1B, and THAP2 in K562-R cells compared with parental K562 cells. Exposing K562-R cells to methylation inhibitors, such as 5-azacytidine (AzaC) and trichostatin A (TSA), reduced imatinib resistance. Our approach of using a drug-limiting dilution model followed by the use of a methylation microarray was able to identify methylation biomarkers for drug resistance. Specifically, MLH1, RPRM, FEM1B, and THAP2 might be potential epigenetic targets of imatinib resistance. Further understanding the methylation domain and epigenetic regulation machinery of these biomarkers will help researchers find potential effective therapeutic strategies that could be used to overcome drug resistance in CML patients.
AB - Drug resistance is an obstacle to successful cancer treatment. In hematological neoplasms, such as chronic myelogenous leukemia (CML), drug resistance is often associated with gene hypermethylation and loss of function. An imatinib-resistant subclone of CML-like K562 (K562-R) was used as a model to study the role of hypermethylation in drug resistance. K562-R was selected by culturing cells with increasing concentrations of imatinib, ranging from 0.2-5 μM. A DNA methylation microarray was performed on the K562-R and parental K562 cells, and selected gene expression levels were confirmed using real-time polymerase chain reaction. The methylation level was significantly increased and the gene expression level significantly was decreased for MLH1, RPRM, FEM1B, and THAP2 in K562-R cells compared with parental K562 cells. Exposing K562-R cells to methylation inhibitors, such as 5-azacytidine (AzaC) and trichostatin A (TSA), reduced imatinib resistance. Our approach of using a drug-limiting dilution model followed by the use of a methylation microarray was able to identify methylation biomarkers for drug resistance. Specifically, MLH1, RPRM, FEM1B, and THAP2 might be potential epigenetic targets of imatinib resistance. Further understanding the methylation domain and epigenetic regulation machinery of these biomarkers will help researchers find potential effective therapeutic strategies that could be used to overcome drug resistance in CML patients.
KW - Chronic myeloid leukemia
KW - Imatinib-resistant
KW - Methylation biomarkers
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U2 - 10.1016/j.gmbhs.2012.04.010
DO - 10.1016/j.gmbhs.2012.04.010
M3 - Article
AN - SCOPUS:84861574264
SN - 2211-4254
VL - 4
SP - 12
EP - 15
JO - Genomic Medicine, Biomarkers, and Health Sciences
JF - Genomic Medicine, Biomarkers, and Health Sciences
IS - 1-2
ER -
