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The role of transcription factor Sp1 in the regulation of gamma-glutamyl hydrolase gene expression by the rs3758149 polymorphism in CEM/C1 cells.

Gamma-Glutamyl hydrolase (GGH) plays an important role in the disposition of anti-folate analogs. Several studies noted the pharmacological relevance of rs3758149 C/T polymorphism located in the human GGH promoter. The present study aimed to investigate the role of rs3758149 C/T polymorphism and transcription factors in the regulation of GGH expression in human acute lymphoblastic leukemia (ALL) CEM/C1 cells. Compared with the rs3758149 T allele, the C allele showed significantly higher transcriptional activity in luciferase reporter assays, as well as a stronger binding affinity for the nuclear protein extracts in an electrophoretic mobility shift assay. Sp1 was identified as the target transcription factor that exhibited allele-specific binding to the location of rs3758149 C/T polymorphism in the chromatin immunoprecipitation assay. Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells. This study contributed to the present understanding of the mechanisms underlying variable responses of ALL to anti-folates.