Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Deoxycytidine kinase is downregulated in Ara-C-resistant acute myeloid leukemia murine cell lines

Leukemia volume 24, pages 1513–1515 (2010)Cite this article

Subjects

Acute myeloid leukemia (AML) is a malignant expansion of immature cells in the bone marrow. Although chemotherapeutic treatments containing cytosine arabinoside (Ara-C) typically result in dramatic remissions, resistance to chemotherapy frequently occurs. Patients presenting with Ara-C-resistant AML have a reduction in the active metabolized form of Ara-C (Ara-CTP), but the mechanisms responsible for this reduction are still being investigated. In previously published work, two AML cell lines (B117P and B140P), derived from BXH-2 strain mouse leukemias, were subjected to increasing concentrations of Ara-C to create two highly resistant derivatives (B117H and B140H) that tolerate Ara-C concentrations ∼800 times that of their parental lines.1 In this study, gene expression microarrays were conducted to determine the expression changes common to both sets of cell lines. The results were verified by quantitative PCR (qPCR) and the specificity of drug resistance was evaluated.

The parental cell lines (B117P and B140P) are markedly different phenotypically and yet their response to Ara-C is about the same with similar 50% inhibitory concentrations (IC50). B117P grows 2.3 times faster than B140P (data not shown), and they have differences in gene expression patterns, as detected by microarray analysis. Although CD34 has not been found to be associated with any particular AML subtype or to be prognostically significant, B117P and B117H highly express Cd34 whereas B140P and B140H do not (a 183-fold difference). Furthermore, the level of myeloperoxidase (Mpo) is 34-fold greater in the B117P cells when compared with the B140P cells. Despite these differences, both cell lines showed some common changes in gene expression on selection for Ara-C resistance. Microarray gene expression analysis to compare differences between the parental cell lines (B117P and B140P) and their highly resistant derivatives (B117H and B140H) was performed on 12 RNA isolations (3 isolations for each cell line from different passages) using Affymetrix (Santa Clara, CA, USA) Mouse Genome 430 2.0 Arrays containing 45 101 murine oligonucleotide sequences. The detection values were processed using Genedata Expressionist software (Genedata AG, Basel, Switzerland) using the robust multiarray average normalization technique. The raw data are available online at http://www.ncbi.nlm.nih.gov/geo/ (accession number GSE18322). Group t-test analysis was used to compare the B117P cells to the B117H cells, and the B140P cells to the B140H cells. Only expression changes greater than 2.0-fold with P-values <0.001 were considered. One hundred and twenty differentially expressed probe sets representing 104 genes were obtained when comparing B140H to B140P. Two hundred and eighty six differentially expressed probe sets representing 239 genes were obtained when comparing B117H to B117P. In Table 1 those genes with consistent expression changes (>2.0-fold) on selection for Ara-C resistance in both cell lines are listed.

Table 1 Common gene expression changes between Ara-C-resistant cell lines and their Ara-C-sensitive parental lines (>2.0-fold)
Full size table

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Yin B, Kogan SC, Dickins RA, Lowe SW, Largaespada DA . Trp53 loss during in vitro selection contributes to acquired Ara-C resistance in acute myeloid leukemia. Exp Hematol 2006; 34: 631–641.

    Article  CAS  PubMed  Google Scholar 

  2. Shi JY, Shi ZZ, Zhang SJ, Zhu YM, Gu BW, Li G et al. Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. Pharmacogenetics 2004; 14: 759–768.

    Article  CAS  PubMed  Google Scholar 

  3. Veuger MJ, Honders MW, Landegent JE, Willemze R, Barge RM . High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia. Blood 2000; 96: 1517–1524.

    CAS  PubMed  Google Scholar 

  4. Song JH, Kim SH, Kweon SH, Lee TH, Kim HJ, Kim HJ et al. Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells. Int J Oncol 2009; 34: 1165–1171.

    CAS  PubMed  Google Scholar 

  5. Jiang Y, Prunier C, Howe PH . The inhibitory effects of disabled-2 (Dab2) on Wnt signaling are mediated through Axin. Oncogene 2008; 27: 1865–1875.

    Article  CAS  PubMed  Google Scholar 

  6. Akyerli CB, Beksac M, Holko M, Frevel M, Dalva K, Ozbek U et al. Expression of IFITM1 in chronic myeloid leukemia patients. Leuk Res 2005; 29: 283–286.

    Article  CAS  PubMed  Google Scholar 

  7. Kongkham PN, Northcott PA, Ra YS, Nakahara Y, Mainprize TG, Croul SE et al. An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma. Cancer Res 2008; 68: 9945–9953.

    Article  CAS  PubMed  Google Scholar 

  8. Chuthapisith S, Bean BE, Cowley G, Eremin JM, Samphao S, Layfield R et al. Annexins in human breast cancer: possible predictors of pathological response to neoadjuvant chemotherapy. Eur J Cancer 2009; 45: 1274–1281.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the Leukemia and Lymphoma Society of America (LLS 7019-04, Specialized Center of Research) and the Leukemia Research Fund (University of Minnesota). We especially thank Teng Zhang for his assistance with the drug assay and Natashay J Bailey for her work on the growth assay.

Author information

Authors and Affiliations

  1. Department of Genetics, Cell Biology, and Development, The Masonic Cancer Center at the University of Minnesota, Minneapolis, MN, USA

    S K Rathe & D A Largaespada

Authors
  1. S K Rathe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D A Largaespada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S K Rathe.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rathe, S., Largaespada, D. Deoxycytidine kinase is downregulated in Ara-C-resistant acute myeloid leukemia murine cell lines. Leukemia 24, 1513–1515 (2010). https://doi.org/10.1038/leu.2010.88

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.88

This article is cited by

Search

Advanced search

Quick links