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Genome-wide DNA methylation profiling of CpG islands in a morpholino anthracycline derivative-resistant leukemia cell line: p38α as a novel candidate for resistance.
Asano, Takeshi; Narazaki, Hidehiko; Fujita, Atsushi.
Afiliação
  • Asano T; Department of Pediatrics Nippon Medical School Tokyo Japan.
  • Narazaki H; Department of Pediatrics Nippon Medical School Tokyo Japan.
  • Fujita A; Department of Pediatrics Nippon Medical School Tokyo Japan.
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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Texto completo: 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

Texto completo: 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