6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner. (February 2012)

• Record Type: Journal Article
• Authors: Kotur, Nikola; Stankovic, Biljana; Kassela, Katerina; Georgitsi, Marianthi; Vicha, Anna; Leontari, Iliana; Dokmanovic, Lidija; Janic, Dragana; Krstovski, Nada; Klaassen, Kristel; Radmilovic, Milena; Stojiljkovic, Maja; Nikcevic, Gordana; Simeonidis, Argiris; Sivolapenko, Gregory; Pavlovic, Sonja; Patrinos, George P; Zukic, Branka
• Is Part Of: Pharmacogenomics. Volume 13:Number 3(2012)
• Page Start: 283
• Page End: 295
• Publication Date: 2012-02
• Subjects: 6-mercaptopurine -- pharmacogenomics -- reporter assay -- TPMT -- TPMT gene promoter -- VNTR; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.11.153
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an An Bm C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription.Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP.Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients. Original submitted 27 July 2011; Revision submitted 24 October 2011