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