Hypermethylation of death-associated protein (DAP) kinase CpG island is frequent not only in B-cell but also in T- and natural killer (NK)/T-cell malignancies

Shin-ichi Nakatsuka; Tetsuya Takakuwa; Yasuhiko Tomita; Yoshihiko Hoshida; Mieko Nishiu; Motoko Yamaguchi; Kazuhiro Nishii; Woo-Ick Yang; Katsuyuki Aozasa

doi:10.1111/j.1349-7006.2003.tb01357.x

Hypermethylation of death-associated protein (DAP) kinase CpG island is frequent not only in B-cell but also in T- and natural killer (NK)/T-cell malignancies

Cancer Sci. 2003 Jan;94(1):87-91. doi: 10.1111/j.1349-7006.2003.tb01357.x.

Authors

Shin-ichi Nakatsuka¹, Tetsuya Takakuwa, Yasuhiko Tomita, Yoshihiko Hoshida, Mieko Nishiu, Motoko Yamaguchi, Kazuhiro Nishii, Woo-Ick Yang, Katsuyuki Aozasa

Affiliation

¹ Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871.

PMID: 12708480
DOI: 10.1111/j.1349-7006.2003.tb01357.x

Abstract

Death-associated protein (DAP) kinase is a pro-apoptotic serine/threonine kinase with a death domain, which is involved in apoptosis induced by interferon-gamma, tumor necrosis factor-alpha, and Fas ligand. Down-regulation of DAP kinase gene expression by hypermethylation of its promoter region might result in resistance to apoptotic cell death, and could provide a basis for tumor development. In the present study, we employed methylation-specific polymerase chain reaction to examine the methylation status of CpG islands in the DAP kinase gene in 19 cases of T-cell malignancies (including eight adult T-cell leukemia/lymphoma), 24 of natural killer (NK)/T-cell, and 34 of B-cell. Frequency of methylation was significantly higher in B-cell (27 of 34, 79.4%) than in T-cell malignancies (nine of 19, 47.4%) (P<0.05). Fifteen of 24 (62.5%) NK/T-cell lymphomas showed DNA methylation. One B-cell lymphoma cell line with DNA methylation was resistant to apoptotic stimuli, and treatment of the cells with a demethylating agent restored apoptotic cell death. These findings suggested that suppression of DAP kinase expression by DNA methylation might play a substantial role in the development of not only B-cell, but also T- and NK/T-cell lymphomas.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / pharmacology
Apoptosis / drug effects
Apoptosis Regulatory Proteins
Azacitidine / analogs & derivatives*
Azacitidine / pharmacology
B-Lymphocytes / enzymology
Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
Calcium-Calmodulin-Dependent Protein Kinases / genetics*
CpG Islands*
DNA Methylation* / drug effects
Death-Associated Protein Kinases
Decitabine
Enzyme Induction
Gene Expression Regulation, Neoplastic*
Hematologic Neoplasms / enzymology
Hematologic Neoplasms / genetics*
Humans
Jurkat Cells / drug effects
Killer Cells, Natural / enzymology
Leukemia-Lymphoma, Adult T-Cell / enzymology
Leukemia-Lymphoma, Adult T-Cell / genetics
Lymphoma, B-Cell / enzymology
Lymphoma, B-Cell / genetics
Lymphoma, T-Cell / enzymology
Lymphoma, T-Cell / genetics
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics*
Neoplastic Stem Cells / enzymology
Promoter Regions, Genetic / genetics*
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes / enzymology
fas Receptor / immunology

Substances

Antibodies, Monoclonal
Apoptosis Regulatory Proteins
Neoplasm Proteins
fas Receptor
Decitabine
Death-Associated Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinases
Azacitidine