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: Hazhar Karim, Jamileh Hashemi, Catharina Larsson, Ali Moshfegh, Alan K Fotoohi, Freidoun Albertioni
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 411 Issue 1 Pg. 156-61 (Jul 22 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21723252 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Mercaptopurine
• DNA Nucleotidylexotransferase
• Thioguanine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• DNA Nucleotidylexotransferase (genetics)
• Drug Resistance, Neoplasm (genetics)
• Gene Dosage
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Humans
• Mercaptopurine (pharmacology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
• Thioguanine (pharmacology)