Chim CS, Liang R, Fung TK, Choi CL, Kwong YL
Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. [Journal Article]
J Clin Pathol 2007 Jun; 60(6):664-9.
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 1 x 10(-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.
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