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.
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.
Nakatsuka
Shin-ichi
S
Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871.
Takakuwa
Tetsuya
T
Tomita
Yasuhiko
Y
Hoshida
Yoshihiko
Y
Nishiu
Mieko
M
Yamaguchi
Motoko
M
Nishii
Kazuhiro
K
Yang
Woo-Ick
WI
Aozasa
Katsuyuki
K
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D064550:Death-Associated Protein Kinases; D000077209:Decitabine; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D007694:Killer Cells, Natural / Q000201:enzymology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000201:enzymology; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D019014:fas Receptor; D000077209:Decitabine; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D001374:Azacitidine