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.


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


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