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Frequent Death-associated Protein Kinase Promoter Hypermethylation in Multiple Myeloma¹

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China

Death-associated protein (DAP) kinase is a novel gene regulating apoptosis induced by IFN-. In B-cell malignancies, loss of DAP kinase expression is commonly associated with promoter hypermethylation. These characteristics of DAP kinase may be of particular relevance in multiple myeloma (MM), a B-lineage malignancy in which prolonged survival capacity of the malignant plasma cells may be critical in the induction and maintenance of tumor cells.

Purpose: The involvement and potential role of DAP kinase in MM pathogenesis was examined.

Experimental Design: In this investigation, methylation-specific PCR was conducted on primary MM and MM cell lines. Methylation status findings were correlated with clinical parameters.

Results: We first demonstrated frequent DAP kinase hypermethylation in 24 of 36 primary MMs (20 of 26 at diagnosis and 4 of 10 with relapse/residual MM after treatment), 1 of 2 patients with monoclonal gammopathy of undetermined significance, and 1 of 3 MM cell lines studied. The high frequency of DAP kinase hypermethylation was similarly observed in MM of different stages, immunoglobulin isotypes, and histological grades, with or without plasmacytomas. Although not statistically significant, the overall survival of patients with DAP kinase methylation was notably shortened among 23 MM patients followed prospectively (P = 0.38 by Kaplan-Meier method and log-rank test). This preliminary finding suggests prognostic implications of DAP kinase in MM that may deserve further investigation.

Conclusions: Our data suggest an important role for DAP kinase in MM tumorigenesis.

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