title: Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene.
abstract: Imatinib induces complete molecular response in patients with chronic myeloid leukemia (CML) and chronic eosinophilic leukemia (CEL). However, development of resistance to imatinib has emerged as an important clinical problem for molecular-targeted therapy in CML and CEL. In this study, we have established the imatinib-resistant CEL EOL-1 sub-lines (designated as EOL-1R) by culturing cells with increasing concentrations of imatinib for 6 months. Interestingly, EOL-1R cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene. Exposure of EOL-1R cells to imatinib failed to dephosphorylate AKT, ERK and STAT5, although PDGFRalpha was effectively inactivated. The forced expression of PTEN negatively regulated these signal pathways and sensitized EOL-1R cells to imatinib. Notably, hypermethylation of the promoter region of the PTEN gene in association with the downregulation of this gene's transcripts was identified in imatinib-resistant leukemia cells isolated from individuals with CEL, CML and Philadelphia-positive acute lymphoblastic leukemia. In addition, anti-epigenetic agents restored PTEN expression, resulting in the sensitization of EOL-1R cells to imatinib. Taken together, epigenetic silence of PTEN is one of the mechanisms that cause drug resistance in individuals with leukemia after exposure to imatinib. Anti-epigenetic agents may be useful for overcoming drug resistance in such a case.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Nishioka
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human