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Chronic Myeloproliferative Disorders

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach

Leukemia volume 20, pages 1047–1054 (2006)Cite this article

Abstract

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR–ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-α treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR–ABL-independent mechanisms.

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Acknowledgements

We thank A Schirenbeck, M Casanova, A Swat and A Greninger for their invaluable help with the reading and analysis of microarrays. We also thank M Navarrete and P de la Cueva for their help with the molecular techniques. We are also grateful to the members of the Departments of Hematology, Cytogenetics and Molecular Biology of the Hospital de la Princesa, the Hospital Ramón y Cajal from Madrid and Hospital Virgen de la Salud, Toledo, especially M Santos-Roncero, E Tejera and E Arranz, for their help with clinical follow-up and samples. We also thank the Tumour Bank Network of the Spanish National Cancer Centre.This work was supported by grants from the Ministerio de Educación y Ciencia (SAF2001-0060 and SAF2004-04286) and from the Ministerio de Sanidad y Consumo (G03/179 and PI052316), Spain, and from NOVARTIS FARMACEUTICA, SA.

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Authors and Affiliations

  1. Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    R Villuendas, L Tracey & M A Piris

  2. Hematology Department, Hospital de la Princesa, Madrid, Spain

    J L Steegmann & A Granda

  3. Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain

    M Pollán

  4. Molecular Biology Department, Hospital de la Princesa, Madrid, Spain

    E Fernández-Ruiz

  5. Hematology Department, Hospital Virgen de la Salud, Toledo, Spain

    L F Casado

  6. Hematology Department, Hospital 12 de Octubre, Madrid, Spain

    J Martínez & P Martínez

  7. Biotechnology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

    L Lombardía

  8. Hematology Department, Hospital Ramón y Cajal, Madrid, Spain

    L Villalón & J Odriozola

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  1. R Villuendas
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Correspondence to R Villuendas.

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Villuendas, R., Steegmann, J., Pollán, M. et al. Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach. Leukemia 20, 1047–1054 (2006). https://doi.org/10.1038/sj.leu.2404197

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