Epigenetic changes in the DAP-kinase CpG island in pediatric lymphoma.
BACKGROUND
Hypermethylation of CpG islands in the promoter region of death-associated protein kinase (DAP-kinase) coupled with the loss of gamma-interferon-induced apoptosis have been reported in B-cell malignancies suggesting a role in pathogenesis or prognosis. Along with B-cell malignancies, pediatric lymphomas also include T-cell non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma, and Hodgkin disease, each with unique prognoses. The purpose of this study was to elucidate epigenetic changes in the DAP-kinase promoter region of pediatric cases to determine associations with aberrant hypermethylation.


METHODS
Thirty-nine cases of different lymphoid pathology [10 Burkitt lymphoma, 1 B-cell NHL; 7 T-cell lymphoblastic lymphoma; 4 anaplastic large cell lymphoma (LCL); 2 B-cell LCL; 14 nodular sclerosing Hodgkin disease (NSHD); and 1 B-cell acute lymphoblastic leukemia (ALL)] had methylation-specific polymerase chain reaction performed on bisulfite-treated DNA, which distinguishes the methylation status of the promoter region, and DAP-kinase mRNA expression assays performed on available specimens.


RESULTS
In normal lymphocytes, the CpG islands in the promoter region were unmethylated, as were the T-cell lymphoblastic lymphoma and anaplastic LCL. In contrast, 100% of the Burkitt lymphoma (10/10) and B-cell ALL (1/1) were hypermethylated. Of the specimens with mRNA available, 7/8 Burkitt lymphoma had no DAP-kinase mRNA expression compared to normal expression in 3/3 and 4/4 T-cell lymphoblastic lymphoma and NSHD, respectively.


CONCLUSIONS
In these pediatric lymphoid tumors, hypermethylation of the DAP-kinase promoter region with associated loss of DAP-kinase gene expression was associated with B-cell malignancies and thus may be important in the development and/or provide a prognostic tool in B- cell lymphomas.
Departments of Pediatrics & Medicine, John A Burns School of Medicine, Pacific Biomedical Research Center, University of Hawaii, Honolulu, USA. bshirami@hawaii.edu
Bruce
B
Shiramizu
Paul
P
Mick
D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002648:Child; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000235:genetics*; D008297:Male; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases