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Chronic Myeloid Leukemia and Myeloproliferative Disorders

Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients

Leukemia volume 20, pages 1400–1407 (2006)Cite this article

Abstract

Although the selective tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia (CML), inherent mechanisms confer primary resistance to leukemic patients. In order to search for potentially useful genes in predicting cytogenetic response, a retrospective gene expression study was performed. Leukocyte RNA isolated before imatinib from interferon-alpha-pretreated chronic phase CML patients (n=34) with or without major cytogenetic remission (⩽35% Philadelphia (Ph)+ metaphases) during the first year of treatment was comparatively analyzed using Affymetrix U133A chips. Using support vector machines for gene classification, an outcome-specific gene expression signature consisting of 128 genes was identified. Comparative expression data of specific genes point to changes in apoptosis (e.g. casp9, tumor necrosis factor receptor-associated protein 1, hras), DNA repair (msh3, ddb2), oxidative stress protection (glutathione synthetase, paraoxonase 2, vanin 1) and centrosomes (inhibitor of differentiation-1) within primary resistant patients. Independent statistical approaches and quantitative real-time reverse transcriptase-polymerase chain reaction studies support the clinical relevance of gene profiling. In conclusion, this study establishes a candidate predictor of imatinib resistance in interferon-alpha-pretreated CML patients to be subjected to future investigation in a larger independent patient cohort. The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance.

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Acknowledgements

This work was supported by the Competence Network ‘Acute and chronic leukemias’ (Grant 01 GI9980/6 from the German Ministry of Education and Research, BMBF and by research funds of the Fakultät für Klinische Medizin Mannheim). We are very grateful for statistical advice by Dr Christel Weiss (Medizinische Statistik, Biomathematik und Informationsverarbeitung, University of Heidelberg, Mannheim, Germany). We thank Maike Haas, Christine Philipps and Christine Folz for excellent technical assistance. Benedikt Brors received funding from the BMBF through the National Genome Research Network (Grant 01 GS 0450).

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Authors and Affiliations

  1. III. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Universitätsklinikum Mannheim der Ruprecht-Karls-Universität Heidelberg, Mannheim, Germany

    O Frank, A Fabarius, U Schwindel, C Zheng, M C Müller, R Hehlmann, A Hochhaus & W Seifarth

  2. Abt. Theoret. Bioinformatik, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

    B Brors

  3. Zentrum für Medizinische Forschung (ZMF), Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany

    L Li, M Haak & N Gretz

  4. Department of Medical Informatics and Biomathematics, University of Muenster, Münster, Germany

    S Merk

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  1. O Frank
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Correspondence to O Frank.

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Frank, O., Brors, B., Fabarius, A. et al. Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients. Leukemia 20, 1400–1407 (2006). https://doi.org/10.1038/sj.leu.2404270

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