Abstract 4330: Transcriptional regulation of gp170 by YY1 and prognostic significance in childhood acute lymphoblastic leukemia (ALL)

Abstract

Abstract Leukemia is the most common cancer among children under the age of 15 years in the United States and many developed countries. In recent years, there has been the emergence of novel therapeutic drugs for this disease. However, the development of drug resistance by the tumor cells remains the most important obstacle in the treatment of leukemia. A widely studied mechanism of tumor resistance to chemotherapeutic drugs is through the expression of the multi-drug resistance (MDR) genes. P-glycoprotein 170 (gp170) is an MDR1 gene product which serves as an ATP-dependent cell membrane transporter; it facilitates the efflux of xenobiotics from the cells to prevent damage for prolonged drug activity, including chemotherapeutics agents. In addition to MDR1, several reports in different cancers have indicated that the transcription factor Yin Yang 1 (YY1) is over-expressed and regulates tumor cell response to chemotherapeutic drugs. TESS analysis demonstrated that the gp170 proximal promoter contains four putative binding sites for the YY-1 protein. We also hypothesized that the YY1 may too be over-expressed in ALL and that its expression may be correlated with the expression of gp170. These hypotheses were examined first by reporter systems analyze, the gp170 protein was cloned and we developed a luciferase reporter assay. Examination of the putative YY1 binding sites that were individually mutated (deleted), showed revealed that mutation at the site –1860 abolished the activity. Mutation at the site –1920 abolished approximately 50% and mutation at –1230 site abolished approximately 25%. Further, CHIP analysis demonstrated that YY1 transcription factor binds directly to the gp170 gene MDR1 promoter. In addition, we examined the expression of YY1 and gp170 in childhood ALL (n= 84). The expression of YY1 and gp170 was determined evaluated by IHC in tumor tissues and the frequency of positive cells was determined. For comparison, normal controls were also analyzed (n=53). The findings demonstrate that were a significant increase in the frequency of positive cells in ALL compared to controls for both YY1 (38% vs. 8%, p=0.001) and for gp170 (42% vs. 12%, p=0.001). There was a good correlation between the expression of YY1 and gp170 (Pearson's test, r=0.4, p=0.001). The findings suggest that YY1 transcriptionally regulates the mdr1 and may be a therapeutic target in MDR positive ALL and its inhibition may reverse resistance to chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4330. doi:1538-7445.AM2012-4330