Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma

Death-associated protein (DAP) kinase is a novel gene regulating apoptosis induced by IFN-gamma, Hn B-cell malignancies, loss of DAP kinase expression is commonly associated with promoter hypermethylation, These characteristi cs 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 cel ls, Purpose: The involvement and potential role of DAP kinase in MM pathogenesi s was examined. Experimental Design: In this investigation, methylation-specific PCR was co nducted on primary MM and MM cell lines, Methylation status findings were c orrelated with clinical parameters. Results: We first demonstrated frequent DBP kinase hypermethylation in 24 o f 36 primary MMs (20 of 26 at diagnosis and 4 of 10 with relapse/residual M M after treatment), 1 of 2 patients with monoclonal gammopathy of undetermi ned significance, and 1 of 3 MM cell lines studied, The high frequency of D AP kinase hypermethylation was similarly observed in MM of different stages , immunoglobulin isotypes, and histological grades, with or without plasmac ytomas, Although not statistically significant, the overall survival of pat ients with DAP kinase methylation was notably shortened among 23 MR;l patie nts followed prospectively (P = 0.38 by Kaplan-Meier method and log-rank te st). This preliminary finding suggests prognostic implications of DAP kinas e in MM that may deserve further investigation Conclusions: Our data suggest an important role for DAP kinase in MM tumori genesis.