Genome-wide DNA methylation profiling of CpG islands in a morpholino anthracycline derivative-resistant leukemia cell line: p38α as a novel candidate for resistance.
Pharmacol Res Perspect
; 5(1): e00285, 2017 02.
Article
em En
| MEDLINE
| ID: mdl-28596837
Effective leukemia treatment is seriously hampered by drug resistance. We previously showed that aberrant methylation of the topoisomerase II α gene causes altered gene expression and acquired drug resistance in etoposide-resistant leukemia cells. In this study, we analyzed the genome-wide methylation status in resistant leukemia cells. We used MX2, which is a morpholino anthracycline derivative that functions as a topoisomerase II α inhibitor. We established a human myelogenous leukemia cell line (K562/P) and a related cell line with resistance to MX2 (K562/MX2). Using these cell lines, we investigated the genome-wide methylation status, compared expression profiles with a microarray, and analyzed the data using Gene Ontology and key node analysis. We demonstrate that the MX2-resistant cell line was globally hypermethylated. Gene Ontology analysis identified genes involved in the immunological response and gene silencing that were responsible for methylation-related altered gene expression in drug-resistant cells. Key node analysis showed that p38α mitogen-activated protein kinase was a novel enzyme involved in MX2-related resistance. p38 kinase activity in resistant cells was increased compared to MX2-sensitive parent cells. Blocking p38α activity using inhibitors and p38α knock down with small interfering RNA restored the sensitivity to MX2 in resistant cells with a decrease in p38 kinase activity as well as decreased expression of p38α mRNA and phosphorylated p38α protein. These findings may lead to a new strategy for treatment of drug-resistant leukemia cells.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Pharmacol Res Perspect
Ano de publicação:
2017
Tipo de documento:
Article