Aberrant methylation of the death‐associated protein kinase 1 (DAPK1) CpG island in chronic myeloid leukemia

Abstract

The death-associated protein kinase 1 (DAPK1) gene is a candidate tumor suppressor (TSG) and the abnormal methylation of DAPK1 gene has been found in many carcinomas. The epigenetic changes of TSGs are now recognized as a mechanism contributing to the development of chronic myeloid leukemia (CML). To clarify the role of DAPK1 in CML, we examined the methylation status of DAPK1 in 49 patients with CML using methylation-specific polymerase chain reaction. The aberrant methylation of the DAPK1 gene was found in 25 of 49 (51.0%) CML cases, not in all controls. No correlation was found between DAPK1 gene methylation and the age, hematologic parameters, chromosomal abnormalities, the types and levels of bcr/abl transcripts of CML patients. However, correlation could be observed between the sex and the status of DAPK1 methylation in CML patients (R = 0.374, P = 0.008). Furthermore, there was a significant correlation between DAPK1 methylation and the stages of CML (R = 0.354, P = 0.013). The CML patients in accelerated phase (AP) and blast crisis (BC) had higher frequency of DAPK1 methylation than those in chronic phase (CP) (75.0% vs. 34.5%) (chi(2) = 7.776, P = 0.005). In one patient, the status of DAPK1 methylation became positive on the transition from CP to AP and BC. These results suggested that DAPK1 promoter methylation might play a significant role in the progression of CML.

Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting

“…The death-associated protein kinase 1 (DAPK1) is part of a 5-member family of proapoptotic serine/threonine kinases that are ubiquitously expressed and are capable of inducing apoptosis. 49 DAPK1 hypermethylation has been specifically linked to pediatric leukemias carrying the MLL-AF4 oncoprotein, 32 the development of chronic lymphocytic leukemia, 50 progression of chronic myeloid leukemia to blast crisis, 33 and several solid tumors. 51,52 This study confirms the previous findings and also suggests that DAPK1 promoter hypermethylation may be a phenomenon of several different MLL translocations.…”

“…PCR was carried out following the protocol written for methylation-specific PCR (MSP) by Licchesi and Herman. 31 MSP primers for DAPK1 CONTROL and p73 CONTROL , 32 DAPK1, 33 and HRK 34 were taken from the published literature. MSP primers for CCR6 were designed using the UCSC Genome Browser human assembly (March 2006).…”

Population-based case–control study on DAPK1, RAR-β2 and MGMT methylation in liquid-based cytology

“…The reaction mixture (20 l) contained 10 ng of templates, 4 pmol of each primer, 4 nmol of dNTP, 1 unit of HotStarTaq DNA polymerase (QIAGEN GmbH, Hilden, Germany) and 2 ml of 10 £ GC-buVer. Primer sequences and PCR conditions for MSP have been reported in previous studies [8][9][10].…”

Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

“…For example, genes that are related to cell cycle regulation such as P16 INK4A and P15 INK4B are silenced in many cancers due to DNA methylation enabling uninhibited proliferation (e.g., [12]). Other genes often hypermethylated, and thus silenced, in cancer can be involved in: cell adhesion, such as E-cadherin and H-cadherin, enabling invasion and/or metastasis of the tumor (e.g., [13]); apoptosis, such as DAPK1, enabling resistance to cell death (e.g., [14]); and finally genes associated with DNA repair processes are also often hypermethylated in tumors, thus suggesting that epigenetic events may promote classical genetic alterations such as mutations.…”