The pattern of gene expression and gene dose profiles of 6-Mercaptopurine- and 6-Thioguanine-resistant human leukemia cells

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• 作者：Hazhar Karim^a ; Jamileh Hashemi^b ; Catharina Larsson^b ; Ali Moshfegh^c ; Alan K. Fotoohi^a ; ^c ; ^{alan.fotoohi@ki.se"" rel=""nofollow} ; Freidoun Albertioni^c
• 关键词：6-Mercaptopurine ; 6-Thioguanine ; Resistance ; Leukemia ; Microarray ; Comparative genomic hybridization
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：22 July 2011
• 年：2011
• 卷：411
• 期：1
• 页码：156-161
• 全文大小：524 K

文摘

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.