title: The pattern of gene expression and gene dose profiles of 6-Mercaptopurine- and 6-Thioguanine-resistant human leukemia cells.
abstract: Exposure of MOLT4 human T-cell leukemia cells to 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) resulted in acquired resistance associated with attenuated expression of the genes encoding concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2). To identify other alterations at the RNA and DNA levels associated with 6-MP- and 6-TG resistance, we compared here the patterns of gene expression and DNA copy number profiles of resistant sublines to those of the parental wild-type cells. The mRNA levels for two nucleoside transporters were down-regulated in both of the thiopurine-resistant sublines. Moreover, both of these cell lines expressed genes encoding the enzymes of purine nucleotide composition and synthesis, including adenylate kinase 3-like 1 and guanosine monophosphate synthetase at significantly lower levels than wild-type cells. In addition, expression of the mRNA for a specialized DNA polymerase, human terminal transferase encoded by the terminal deoxynucleotidyl transferase (DNTT) gene, was 122- and 93-fold higher in 6-TG- and 6-MP-resistant cells, respectively. The varying responses to 6-MP- and 6-TG observed here may help identify novel cellular targets and modalities of resistance to thiopurines, as well as indicating new potential approaches to individualization therapy with these drugs.
authors: Department of Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Hazhar
authors: H
authors: Karim
authors: Jamileh
authors: J
authors: Hashemi
authors: Catharina
authors: C
authors: Larsson
authors: Ali
authors: A
authors: Moshfegh
authors: Alan K
authors: AK
authors: Fotoohi
authors: Freidoun
authors: F
authors: Albertioni
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004253:DNA Nucleotidylexotransferase / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015122:Mercaptopurine / Q000494:pharmacology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D013866:Thioguanine / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D004253:DNA Nucleotidylexotransferase; D013866:Thioguanine