Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes.
Death-associated protein kinase (DAP-kinase), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by polymerase chain reaction (PCR). Hypermethylation of DAP-kinase was present in 27.5% (44 of 160) of AML and in 47% (16 of 34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (P =.008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML; 14 of 29, 48.3%), as compared to de novo AML (30 of 131, 22.9%, P =.01). DAP-kinase hypermethylation in AML was associated with myelodysplastic changes in the bone marrow at the time of the initial diagnosis (P =.002) and with the presence of cytogenetic abnormalities (P =.02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.
D000368:Aged; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D064550:Death-Associated Protein Kinases; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000628:therapy; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000201:enzymology* / Q000628:therapy; D016133:Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases