Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

Abstract

Background: Dysregulation of apoptosis is important in carcinogenesis. Aim and Methods: To analyse the potential inactivation of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway by aberrant promoter methylation in acute leukaemias. Results: Of five leukaemic lines examined, p14 was unmethylated in Raji, HL60 and U937, but completely deleted in Jurkat and NB4. DAP kinase was totally methylated in Raji and NB4, but unmethylated in HL60, Jurkat and U937. Apaf-1 was unmethylated in all the lines. At diagnosis, DAP kinase methylation occurred in eight (25%) APL patients and none of the other AML patients (8/32 vs 0/50, p = 0.001). DAP kinase methylation was detected in four (16%) ALL patients. p14 and Apaf-1 methylation was not detected in any of the 32 cases of acute promyelocytic leukaemia (APL), 50 cases of other subtypes of acute myeloid leukaemia (AML), and 25 cases of acute lymphoblastic leukaemia. Conclusion: Among AML subtypes, DAP kinase is preferentially hypermethylated in APL.