Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells.
Resistance to cytarabine (Ara-C) incapacitates the therapeutic effort during the treatment of acute myeloid leukemia (AML). To elucidate mechanism responsible for the development of resistance to Ara-C, we established the Ara-C resistant AML-2/WT cell sublines, AML-2/IDAC and AML-2/ARC. We then conducted DNA microarray analysis to compare the AML-2/IDAC cells with parental AML-2/WT cells. The results of the microarray analysis revealed a severe defect in the expression of deoxycytidine kinase (dCK), which plays a key role in the transformation of Ara-C to the active form in AML-2/IDAC cells. A similar event was observed in AML-2/ARC cells, but not in Ara-C sensitive AML-2/IDA cells that were resistant to idarubicin. The decreased expression of dCK also resulted in lower activity in both Ara-C resistant variants. However, no significant difference in the intracellular concentration of Ara-C was observed among the cells tested, which indicates that the Ara-C resistant phenotype in our models occurred due to the lower expression and activity of dCK rather than a change in the ability to take up Ara-C. Additionally, in vitro assays using BM cells from AML patients revealed that the expression of dCK and the sensitivity to Ara-C were correlated. Taken together, these findings demonstrate that dCK can regulate the in vitro cellular response to Ara-C in AML cells.
Song
Ju Han
JH
Division of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Kim
Seung Hyun
SH
Kweon
Sin Ho
SH
Lee
Tae Hyang
TH
Kim
Hee-Je
HJ
Kim
Hyeoung-Joon
HJ
Kim
Tae Sung
TS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D053938:DNA Fragmentation; D003842:Deoxycytidine Kinase / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003842:Deoxycytidine Kinase