[Hypermethylation of DAP-kinase gene CpG Island in malignant lymphoma with B-cell phenotype].
Death-associated protein-kinase(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. Epigenetic down-regulation of DAP-Kinase gene expression by hypermethylation of its promoter region was reported in certain kinds of malignancies. Previous patho-epidemiological studies indicated that thyroid lymphoma(TL) evolves among active lymphoid cells in chronic lymphocytic thyroiditis(CLTH). With the use of methylation specific polymerase chain reaction, methylation status of DAP-Kinase CpG island was examined in thyroid lesions of 19 cases with TL and 9 with CLTH. Frequency of methylation was higher in TL cases(16 of 19, 84.2%) than in CLTH cases(2 of 9, 22.2%) (p < 0.01). DNA extracted from peripheral blood leukocytes from TL and CLTH cases never showed methylation, indicating that the methylation occurred somatically in lesional lymphocytes in the thyroid. We also examined the methylation status of DAP-kinase gene in 16 cases of T-cell malignancies including eight adult T-cell leukemia/lymphoma and 24 NK/T-cell, 34 B-cell, and two immunophenotypically undetermined lymphomas. Frequency of methylation was higher in B-cell(27 of 34, 79.4%) than in T-cell malignancies(eight of 16, 50%) (p < 0.05). Fifteen of 24(62.5%) NK/T-cell lymphomas showed DNA methylation. Hematopoietic cell lines with a methylated gene were resistant to apoptosis. Treatment of the cells with a demethylating agent restored apoptotic cell death in one B-cell lymphoma cell line with DNA methylation. Our results suggested that suppression of DAP-Kinase expression by DNA methylation might play a role in the development of B-cell malignancies.
Nakatsuka
S
S
Department of Pathology, Osaka University Graduate School of Medicine, Suita 565-0871.
Takakuwa
T
T
Aozasa
K
K
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases