Hypermethylation of the DAP-Kinase CpG Island Is a Common Alteration in B-Cell Malignancies

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Abstract
Death-associated protein kinase (DAP-Kinase) is a novel serine/threonine kinase whose expression is required for γ interferon-induced apoptosis. A previous study suggested that DAP-Kinase expression may be lost epigenetically in cancer cell lines, because treatment of several nonexpressing cell lines with 5-aza-2′-deoxycytidine resulted in the expression of DAP-Kinase. Using methylation-specific polymerase chain reaction (MSP), we examined the DAP-Kinase CpG island for hypermethylation in cancer. Normal lymphocytes and lymphoblastoid cell lines are unmethylated in the 5′ CpG island of DAP-Kinase. However, in primary tumor samples, all Burkitt’s lymphomas and 84% of the B-cell non-Hodgkin’s lymphomas were hypermethylated in the DAP-Kinase CpG island. In contrast, none of the T-cell non-Hodgkin’s lymphoma samples and 15% or less of leukemia samples examined had hypermethylated DAP-Kinase alleles. U937, an unmethylated, DAP-Kinase–expressing leukemia cell line, was treated with γ interferon and underwent apoptosis; however, Raji, a fully methylated, DAP-Kinase nonexpressing Burkitt’s lymphoma cell line, only did so when treated with 5-aza-2′-deoxycytidine followed by γ interferon. Our findings in cell lines and primary tumors suggest that hypermethylation of the DAP-Kinase gene and loss of γ interferon-mediated apoptosis may be important in the development of B-cell malignancies and may provide a promising biomarker for B-cell–lineage lymphomas.