ORIGINAL ARTICLE
Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma
University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
Correspondence to:
Correspondence to:
Dr C-S Chim
Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong 852, Hong Kong; jcschim{at}hku.hk or ylkwong{at}hku.hk
Aim: To study the role of gene promoter hypermethylation of the putative tumour suppressor genes involved in the death-associated protein (DAP) kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma (MM).
Method: DNAs from 55 primary MM marrow samples and myeloma cell lines were analysed for aberrant promoter methylation of DAP kinase, p14 and Apaf-1 genes by methylation-specific polymerase chain reaction (MSP).
Result: In the methylated positive control, the sensitivity of M-MSP for DAP kinase was 1x10–3. Aberrant hypermethylation of DAP kinase was found in 29/55 (52.7%) primary MM samples, whereas hypermethylation of p14 or Apaf-1 was undetectable in any of the samples tested. 5-Azacytidine treatment of two myeloma cell lines, WL2 and HS-Sultan, led to de-methylation and re-expression of DAP kinase, thereby confirming gene silencing associated with promoter hypermethylation. Hypermethylation of DAP kinase did not correlate with age, sex, paraprotein subtype or Durie–Salmon stage, but negatively affected the overall survival.
Conclusion: Of the putative tumour suppressor genes in the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway, only DAP kinase is frequently methylated in MM, which is associated with gene silencing and might be of prognostic significance. p14 and Apaf-1 were not methylated in MM.
Abbreviations: 5-AC, 5-azacytidine; DAP, death-associated protein; HSCT, haematopoietic stem cell transplantation; MM, multiple myeloma; MSP, methylation-specific polymerase chain reaction; OS, overall survival
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