Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias.
BACKGROUND
Dysregulation of apoptosis is important in carcinogenesis.


OBJECTIVE
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.


CONCLUSIONS
Among AML subtypes, DAP kinase is preferentially hypermethylated in APL.
Chim
C S
CS
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. jcschim@hku.hk
Chan
W W L
WW
Kwong
Y L
YL
D000208:Acute Disease; D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D009363:Neoplasm Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D064550:Death-Associated Protein Kinases