title: Methylation analysis of the DAPK1 gene in imatinib-resistant chronic myeloid leukemia patients.
abstract: Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic gene that induces cellular apoptosis in response to internal and external apoptotic stimulants. The silencing ofDAPK1can result in uncontrolled cell proliferation, indicating that it may have a role in tumor suppression.DAPK1activity can be inhibited by the cytosine methylation that occurs in its promoter region. These methylation changes in the promoter region ofDAPK1have been reported in a range of solid and hematological malignancies. In the present study,DAPK1methylation was investigated in chronic myeloid leukemia patients (n=43) using bisulfite conversion followed by methylation-specific polymerase chain reaction. The present study included a number of patients who were identified to be resistant to the common chemotherapeutic agent imatinib (STI571, Gleevec®, Glivec®), exhibiting at least one mutation in the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) gene. Thus, the patients in the present study were divided into two groups according to their response to imatinib therapy: Non-resistant (n=26) and resistant (n=17) to imatinib. Resistant patients were characterized by the presence of single or multiple mutations of theBCR-ABLgene: i) T315I, ii) M351T, iii) E255K, iv) T315I and M351T or v) T315I, M351T and E255K. The present study identified that: i) The incidence ofDAPK1methylation was significantly higher in the resistant patients compared with the non-resistant patients; ii) the extent of resistance varied between mutation types; and iii) there was noDAPK1methylation in any of the healthy controls. These findings indicate thatDAPK1methylation may be associated with a signaling pathway for imatinib resistance in chronic myeloid leukemia.
authors.affiliation: Department of Basic Biotechnology, Institute of Biotechnology, Ankara University, Golbasi, Ankara 06830, Turkey.
authors.forename: Selcen
authors.initials: S
authors.lastname: Celik
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey ; Department of Biology, Faculty of Arts and Sciences, Mehmet Akif Ersoy University, Burdur 15100, Turkey.
authors.forename: Dilara
authors.initials: D
authors.lastname: Akcora
authors.affiliation: Department of Basic Biotechnology, Institute of Biotechnology, Ankara University, Golbasi, Ankara 06830, Turkey.
authors.forename: Tulin
authors.initials: T
authors.lastname: Ozkan
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey.
authors.forename: Nuray
authors.initials: N
authors.lastname: Varol
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey.
authors.forename: Sena
authors.initials: S
authors.lastname: Aydos
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey.
authors.forename: Asuman
authors.initials: A
authors.lastname: Sunguroglu
keywords: DAPK1; DNA methylation; chronic myeloid leukemia; imatinib resistance; methylation-specific polymerase chain reaction