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Sensitivity and Resistance to Therapy

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance

Leukemia volume 20, pages 820–826 (2006)Cite this article

Abstract

The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A case–control study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosin-containing protein was chosen for validation and quantification by Western blot analysis in a second case–control group of ALL patients. In this second independent cohort, median VCP expression (P25–P75) was 0.15 (0.11–0.28) in PGR and 0.34 (0.14–0.99) in PPR patients (P=0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.

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Acknowledgements

We thank Christian Obermaier for his kind and competent support establishing the 2-DE in our laboratory and Girmay Asgedom, Astrid Sundmacher and Silja Roettgers for their excellent technical assistance. This study was supported by the Deutsche Leukämie Forschungshilfe, the Madeleine-Schickedanz-Kinderkrebsstiftung, Erich und Emmy Hoselmann-Stiftung and the Deutsche José Carreras Leukämie-Stiftung (DJCLS R05/16v).

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Authors and Affiliations

  1. Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology and Oncology, University of Freiburg, Freiburg, Germany

    M Lauten

  2. Department of Paediatrics, Christian-Albrechts-University Kiel, Kiel, Germany

    A Schrauder & M Schrappe

  3. Hannover Medical School, Paediatric Haematology and Oncology, Hannover, Germany

    M Lauten, C Kardinal & K Welte

  4. Oncogenetic Laboratory, Children's Hospital, Justus-Liebig-University, Giessen, Germany

    J Harbott

  5. Hannover Medical School, Institute of Cell and Molecular Pathology, Hannover, Germany

    B Schlegelberger & N von Neuhoff

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Correspondence to M Lauten.

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

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Lauten, M., Schrauder, A., Kardinal, C. et al. Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance. Leukemia 20, 820–826 (2006). https://doi.org/10.1038/sj.leu.2404162

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