Purpose: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML.
Experimental Design: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes.
Results: Two SNPs were identified within the PDCD5 promoter. They are -27A>G and -11G>A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of -27G+/-11A+ genotype and -27G/-11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, chi2=11.75, P<0.01; allele: 13.57% versus 6.40%, chi2=9.48, P<0.01). Luciferase reporter assays revealed that the promoter with -27G/-11A had significantly lower transcriptional activity and could not be up-regulated after apoptotic stimulations compared with the promoter with -27A/-11G. PDCD5 expression analysis in mononuclear cells derived from CML patients and cell lines with different -27/-11 genotypes showed consistent results with the reporter assays.
Conclusions: These data suggest that -27G/-11A is associated with reduced PDCD5 promoter activity and increased susceptibility to CML.
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