Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells

Ju Han Song, Seung Hyun Kim, Sin Ho Kweon, Tae Hyang Lee, Hee Je Kim, Hyeoung Joon Kim, Tae Sung Kim

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1165-1171
Number of pages7
JournalInternational Journal of Oncology
Volume34
Issue number4
DOIs
Publication statusPublished - 2009 Jul 3

Fingerprint

Deoxycytidine Kinase
Cytarabine
Myeloid Cells
Acute Myeloid Leukemia
AIDS-Related Complex
Microarray Analysis
Idarubicin
Oligonucleotide Array Sequence Analysis

Keywords

  • Acute myeliod leukemia
  • Cytarabine
  • Deoxycytidine kinase
  • Drug-resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells. / Song, Ju Han; Kim, Seung Hyun; Kweon, Sin Ho; Lee, Tae Hyang; Kim, Hee Je; Kim, Hyeoung Joon; Kim, Tae Sung.

In: International Journal of Oncology, Vol. 34, No. 4, 03.07.2009, p. 1165-1171.

Research output: Contribution to journalArticle

Song, Ju Han ; Kim, Seung Hyun ; Kweon, Sin Ho ; Lee, Tae Hyang ; Kim, Hee Je ; Kim, Hyeoung Joon ; Kim, Tae Sung. / Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells. In: International Journal of Oncology. 2009 ; Vol. 34, No. 4. pp. 1165-1171.
@article{026bda0ad9c3448d947f02151916640c,
title = "Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells",
abstract = "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.",
keywords = "Acute myeliod leukemia, Cytarabine, Deoxycytidine kinase, Drug-resistance",
author = "Song, {Ju Han} and Kim, {Seung Hyun} and Kweon, {Sin Ho} and Lee, {Tae Hyang} and Kim, {Hee Je} and Kim, {Hyeoung Joon} and Kim, {Tae Sung}",
year = "2009",
month = "7",
day = "3",
doi = "10.3892/ijo_00000245",
language = "English",
volume = "34",
pages = "1165--1171",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "4",

}

TY - JOUR

T1 - Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells

AU - Song, Ju Han

AU - Kim, Seung Hyun

AU - Kweon, Sin Ho

AU - Lee, Tae Hyang

AU - Kim, Hee Je

AU - Kim, Hyeoung Joon

AU - Kim, Tae Sung

PY - 2009/7/3

Y1 - 2009/7/3

N2 - 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.

AB - 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.

KW - Acute myeliod leukemia

KW - Cytarabine

KW - Deoxycytidine kinase

KW - Drug-resistance

UR - http://www.scopus.com/inward/record.url?scp=67649449952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649449952&partnerID=8YFLogxK

U2 - 10.3892/ijo_00000245

DO - 10.3892/ijo_00000245

M3 - Article

VL - 34

SP - 1165

EP - 1171

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 4

ER -