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  • Original Article
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Chronic Myeloproliferative Disorders

Gene expression signatures associated with the resistance to imatinib

Leukemia volume 20, pages 1542–1550 (2006)Cite this article

Abstract

Imatinib (imatinib mesylate, STI-571, Gleevec) is a selective BCR-ABL tyrosine kinase inhibitor that has been used as a highly effective chemoagent for treating chronic myelogenous leukemia. However, the initial response to imatinib is often followed by the recurrence of a resistant form of the disease, which is major obstacle to many therapeutic modalities. The aim of this study was to identify the gene expression signatures that confer resistance to imatinib. A series of four resistant K562 sublines was established with different imatinib dosage (200, 400, 600 and 800 nM) and analyzed using microarray technology. The transcripts of the genes showing universal or dose-dependent expression changes across the resistant sublines were identified. The gene sets associated with the imatinib-resistance were also identified using gene set enrichment analysis. In the resistant K562 sublines, the transcription- and apoptosis-related expression signatures were upregulated, whereas those related to the protein and energy metabolism were downregulated. Several genes identified in this study such as IGF1 and RAB11A have the potential to become surrogate markers useful in a clinical evaluation of imatinib-resistant patients without BCR-ABL mutation. The expression signatures identified in this study provide insights into the mechanism of imatinib-resistance and are expected to facilitate the development of an effective diagnostic and therapeutic strategy.

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Acknowledgements

We thank the Korean Leukemia Cell and Gene Bank for providing the imatinib-resistant CML samples and S Yim for critical appraisal of this paper. This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (0405-BC02-0604-0004), the Catholic Medical Center Research Foundation (2004) and Ministry of Science and Technology (2004-01303; M1-0416-22-0006), Republic of Korea.

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  1. Y-J Chung and T-M Kim: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Y-J Chung, T-M Kim & H-M Kang

  2. Department of Internal medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

    D-W Kim

  3. Molecular Genetic Laboratory, College of Medicine, The Catholic University of Korea, Seoul, Korea

    H Namkoong, H K Kim, S-A Ha, S Kim, S M Shin & J W Kim

  4. Seoul National University Biomedical Informatics (SNUBI) and Human Genome Research Institute, College of Medicine, Seoul National University, Seoul, Korea

    J-H Kim & Y-J Lee

  5. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea

    J W Kim

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Correspondence to J W Kim.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chung, YJ., Kim, TM., Kim, DW. et al. Gene expression signatures associated with the resistance to imatinib. Leukemia 20, 1542–1550 (2006). https://doi.org/10.1038/sj.leu.2404310

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