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 of DAPK1 can result in uncontrolled cell proliferation, indicating that it may have a role in tumor suppression. DAPK1 activity can be inhibited by the cytosine methylation that occurs in its promoter region. These methylation changes in the promoter region of DAPK1 have been reported in a range of solid and hematological malignancies. In the present study, DAPK1 methylation 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 the BCR-ABL gene: i) T315I, ii) M351T, iii) E255K, iv) T315I and M351T or v) T315I, M351T and E255K. The present study identified that: i) The incidence of DAPK1 methylation 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 no DAPK1 methylation in any of the healthy controls. These findings indicate that DAPK1 methylation may be associated with a signaling pathway for imatinib resistance in chronic myeloid leukemia.

Highlights

  • The death‐associated protein kinase‐1 (DAPK1) gene is localized to chromosome 9q34.1 and encodes a 160‐kDa serine/threonine, microfilament‐bound kinase which is involved in interferon‐γ, tumor necrosis factor‐α and Fas ligand‐induced apoptosis, anoikis and autophagic cell death, respectively [1,2,3,4]

  • The present study aimed to investigate whether DAPK1 methylation occurs in chronic myeloid leukemia (CML) patients with or without imatinib resistance, and identified that: i) The DAPK1 promoter was significantly methylated in CML patients (10/43) compared with healthy individuals (0/25); ii) the proportion of imatinib‐resistant CML patients demonstrating DAPK1 methylation (6/17) was higher than the proportion of non‐resistant CML patients demonstrating DAPK1 methylation (4/26); and iii) the incidence of DAPK1 methylation in resistant patients varied between the different types of breakpoint cluster region (BCR)‐Abelson murine leukemia (ABL) mutation

  • The results of the present study indicate that DAPK1 methylation may be associated with resistance to imatinib therapy in CML patients; this is dependent on the type of mutation causing the resistance

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Summary

Introduction

The death‐associated protein kinase‐1 (DAPK1) gene is localized to chromosome 9q34.1 and encodes a 160‐kDa serine/threonine, microfilament‐bound kinase which is involved in interferon‐γ, tumor necrosis factor‐α and Fas ligand‐induced apoptosis, anoikis and autophagic cell death, respectively [1,2,3,4]. DNA methylation is hypothesized to be involved in transcriptional silencing [8], and loss of DNA methylation appears to be associated with cellular differentiation [9,10,11] and cancer growth [12,13,14] Specific agents, such as 5‐azacytidine and 5‐aza‐2'‐deoxycytidine (decitabine), inhibit DNA methylation by blocking DNMT activity [15,16] and have been proposed for use in cancer therapy [15,17,18,19]. The results of the present study indicate that DAPK1 methylation may be associated with resistance to imatinib therapy in CML patients; this is dependent on the type of mutation causing the resistance

Materials and methods
Results
Gozuacik D and Kimchi A
Raveh T and Kimchi A
30. Walz C and Sattler M
49. Cilloni D and Saglio G: Molecular pathways
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