6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner.
OBJECTIVE
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 A(n)B(m)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.


CONCLUSIONS
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.
Institute of Molecular Genetics & Genetic Engineering, University of Belgrade, Laboratory for Molecular Hematology, Belgrade 11010, Serbia.
Nikola
N
Kotur
Biljana
B
Stankovic
Katerina
K
Kassela
Marianthi
M
Georgitsi
Anna
A
Vicha
Iliana
I
Leontari
Lidija
L
Dokmanovic
Dragana
D
Janic
Nada
N
Krstovski
Kristel
K
Klaassen
Milena
M
Radmilovic
Maja
M
Stojiljkovic
Gordana
G
Nikcevic
Argiris
A
Simeonidis
Gregory
G
Sivolapenko
Sonja
S
Pavlovic
George P
GP
Patrinos
Branka
B
Zukic
D000483:Alleles; D005838:Genotype; D006801:Humans; D020014:K562 Cells; D015122:Mercaptopurine / Q000494:pharmacology*; D008780:Methyltransferases / Q000235:genetics*; D018598:Minisatellite Repeats / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase