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
  • Published:

Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells

Nature Genetics volume 34, pages 85–90 (2003)Cite this article

An Erratum to this article was published on 01 June 2003

Abstract

To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.

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

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: Leave-one-out cross-validation and permutation test.
Figure 2: Gene Ontology classifications of the genes discriminating among treatments.
Figure 3: Supervised hierarchical clustering and principal component analysis using selected genes.
Figure 4: Hierarchical clustering of relative change in gene expression using the 150 most discriminating gene probe sets selected by LDA.
Figure 5: The top ten discriminating genes for each treatment, identified by distinction calculation.
Figure 6: The number of genes upregulated or downregulated (by at least 50%) in at least 70% of individuals after treatment with methotrexate alone (HDMTX; orange), mercaptopurine alone (MP; green) or the combination of the drugs (HDMTX+MP).

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Pui, C.H. & Evans, W.E. Acute lymphoblastic leukemia. N. Engl. J. Med. 339, 605–615 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Evans, W.E. & Relling, M.V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Evans, W.E. & McLeod, H.L. Pharmacogenomics—drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Pui, C.H., Campana, D. & Evans, W.E. Childhood acute lymphoblastic leukaemia—current status and future perspectives. Lancet Oncol. 2, 597–607 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Armstrong, S.A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30, 41–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Ferrando, A.A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Yeoh, E.-J. et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1, 133–143 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Scherf, U. et al. A gene expression database for the molecular pharmacology of cancer. Nat. Genet. 24, 236–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Tsurusawa, M., Saeki, K. & Fujimoto, T. Differential induction of apoptosis on human lymphoblastic leukemia Nalm-6 and Molt-4 cells by various antitumor drugs. Int. J. Hematol. 66, 79–88 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Elion, G.B. The purine path to chemotherapy. Science 244, 41–47 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kastan, M.B. & Lim, D.S. The many substrates and functions of ATM. Nat. Rev. Mol. Cell Biol. 1, 179–186 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Baskaran, R. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516–519 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Li, J.C. & Kaminskas, E. Accumulation of DNA strand breaks and methotrexate cytotoxicity. Proc. Natl. Acad. Sci. USA 81, 5694–5698 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lorico, A. et al. Accumulation of DNA strand breaks in cells exposed to methotrexate or N10-propargyl-5,8-dideazafolic acid. Cancer Res. 48, 2036–2041 (1988).

    CAS  PubMed  Google Scholar 

  17. Nelson, W.G. & Kastan, M.B. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol. Cell Biol. 14, 1815–1823 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bakkenist, C.J. & Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Wijnen, J. et al. Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15–16. Am. J. Hum. Genet. 58, 300–307 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Palmirotta, R. et al. Transcripts with splicings of exons 15 and 16 of the hMLH1 gene in normal lymphocytes: implications in RNA-based mutation screening of hereditary non-polyposis colorectal cancer. Eur. J. Cancer 34, 927–930 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Gong, J.G. et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806–809 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Swann, P.F. et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273, 1109–1111 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Marton, M.J. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nat. Med. 4, 1293–1301 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Sotiriou, C. et al. Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer. Breast Cancer Res. 4, R3 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bokkerink, J.P. et al. 6-Mercaptopurine: cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem. Pharmacol. 45, 1455–1463 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Gorlick, R. et al. Intrinsic and acquired resistance to methotrexate in acute leukemia. N. Engl. J. Med. 335, 1041–1048 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Masson, E. et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate. J. Clin. Invest. 97, 73–80 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Synold, T.W. et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J. Clin. Invest. 94, 1996–2001 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lipshutz, R.J., Fodor, S.P., Gingeras, T.R. & Lockhart, D.J. High density synthetic oligonucleotide arrays. Nat. Genet. 21, 20–24 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the technical support of K. Brown, C. Ding, J. Morris, D. Patel, M. Shipman and M. Wilkinson, and we thank M. Caldwell and N. Kornegay for help in preparing the manuscript and establishing our research databases. The authors also thank C. Sherr, J. Cleveland, T. Curran, B. Schulman and M. Kastan for providing critical feedback, S. Shurtleff for contributions to gene expression analysis and R. Ashmun for flow cytometric analysis. This work was supported by grants from the US National Institutes of Health to W.E.E., M.V.R. and J.R.D., by a Cancer Center Support Grant from the US National Cancer Institute, by a F.M. Kirby Clinical Research Professorship from the American Cancer Society to C.H.P., by a stipend from the Dr. Hilmer Foundation, German Science Foundation to M.H.C., and by the American Lebanese Syrian Associated Charities.

Author information

Authors and Affiliations

  1. The Hematological Malignancies Program: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, 38105, Tennessee, USA

    Meyling H. Cheok, Wenjian Yang, Mary V. Relling & William E. Evans

  2. The University of Bonn, Germany

    Meyling H. Cheok

  3. Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Ching-Hon Pui

  4. The University of Tennessee, Memphis, USA

    Ching-Hon Pui, Mary V. Relling & William E. Evans

  5. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    James R. Downing

  6. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Cheng Cheng

  7. The Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Clayton W. Naeve

Authors
  1. Meyling H. Cheok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenjian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ching-Hon Pui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James R. Downing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Clayton W. Naeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary V. Relling
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William E. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William E. Evans.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheok, M., Yang, W., Pui, CH. et al. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet 34, 85–90 (2003). https://doi.org/10.1038/ng1151

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1151

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing