Molecular mechanisms of Survivin gene expression regulated by imatinib / 白血病·淋巴瘤

ABSTRACT

Objective To investigate the influences of imatinib on Survivin gene expression in bcr-abl-transformed leukemia cells.Methods Firstly,PCR and Western blot were carried out to detected Survivin expression with imatinib treatment in 32Dcl3 and 32D-bcr-abl cell lines.Then the luciferase reporter plasmids containing human Survivin promoter as well as its deletion and site-directed mutation were constructed to identify the essential responsive elements for suppressing Survivin promoter activity by imatinib.Chromatin immunoprecipitation was performed to confirm the binding of c-myc to Survivin promoter.10058-F4,a small molecule c-myc inhibitor,was used to disrupt c-myc activity and evaluate its anti-leukemic effect combined with imatinib.Results Both of mRNA and protein level of Survivin in bcr-abl-transformed cells were downregulated upon imatinib treatment.The decrease of Survivin expression was controlled at the transcriptional level through a mechanism in which imatinib repressed survivin promoter activity by disturbing the interaction between c-myc and E-box elements.Interruption of c-myc activity by 10058-F4 exerted an anti-leukemia effect with enhancing the sensibility of K562/G01 cells to imatinib.Conclusion Imatinib down-regulates Survivin expression through c-myc-mediated transcription and interference with c-myc might be a potential utility for treatment of imatinib resistant leukemia.