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Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma
1Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China. margaretng@cuhk.edu.hk
Unlabelled:
Death-associated protein (DAP) kinase is a novel gene regulating apoptosis induced by IFN-gamma. 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.
Insights
Death-associated protein (DAP) kinase hypermethylation is frequent in multiple myeloma (MM), a B-cell malignancy. This epigenetic alteration may play a role in MM pathogenesis and warrants further investigation for prognostic implications.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Death-associated protein (DAP) kinase regulates apoptosis and its loss is linked to promoter hypermethylation in B-cell malignancies.
- Multiple myeloma (MM) is a B-lineage malignancy characterized by prolonged survival of malignant plasma cells.
- DAP kinase's role in MM pathogenesis is of significant interest due to its potential impact on tumor cell survival.
Purpose of the Study:
- To investigate the involvement and potential role of DAP kinase in the pathogenesis of multiple myeloma.
- To examine the frequency of DAP kinase hypermethylation in primary MM samples and MM cell lines.
Main Methods:
- Methylation-specific PCR was employed to assess DAP kinase promoter methylation status.
- Primary MM samples and MM cell lines were analyzed.
- Methylation status was correlated with clinical parameters and patient survival.
Main Results:
- Frequent DAP kinase hypermethylation was observed in 24 of 36 primary MM cases (67%) and 1 of 3 MM cell lines.
- Hypermethylation was also found in one patient with monoclonal gammopathy of undetermined significance.
- A trend towards shortened overall survival was noted in MM patients with DAP kinase methylation, though not statistically significant (P=0.38).
Conclusions:
- The study suggests a significant role for DAP kinase in the tumorigenesis of multiple myeloma.
- Frequent hypermethylation of DAP kinase in MM indicates its potential involvement in disease development.
- Further research is warranted to explore the prognostic implications of DAP kinase methylation in MM.