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Initial leukemic gene expression profiles of patients with poor in vivo prednisone response are similar to those of blasts persisting under prednisone treatment in childhood acute lymphoblastic leukemia

Annals of Hematology volume 87, Article number: 709 (2008) Cite this article

Abstract

Response to initial glucocorticoid (GC) treatment is a strong prognostic factor in childhood acute lymphoblastic leukemia (ALL). Patients with a poor prednisone response (PPR) have a poor event-free survival as compared to those with a good prednisone response (PGR). Causes of prednisone resistance are still not well understood. We hypothesized that GC resistance is an intrinsic feature of ALL cells which is reflected in the gene expression pattern and analyzed genome-wide gene expression using microarrays. A case–control study was performed comparing gene expression profiles from initial ALL samples of 20 patients with PPR and those of 20 patients with PGR. Differential gene expression of a subset of genes was confirmed by real-time quantitative polymerase chain reaction analysis and validation was performed in a second independent patient sample (n = 20). We identified 121 genes that clearly distinguished prednisone-resistant from sensitive ALL samples (FDR < 5%, fold change ≥1.5). Differential gene expression of 21 of these genes could be validated in a second independent set. Of importance, there was a remarkable concordance of genes identified by comparing expression signatures of PPR and PGR cells at diagnosis and those previously described to be up- or downregulated in leukemic cells persisting under GC treatment. Thus, GC resistance seems at least in part to be an intrinsic feature of leukemic cells. Leukemic cells of patients with PPR are characterized by gene expression pattern which are similar to those of resistant cells persisting under glucocorticoid treatment.

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Acknowledgments

We thank all patients, nurses, and physicians for their participation in ALL-BFM 2000. This study was supported by the Young Investigator Faculty Grant (Kiel) and the Bundesministerium für Bildung und Forschung (BMBF).

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Affiliations

  1. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105, Kiel, Germany

    Gunnar Cario, Andrea Fetz, Christian Bretscher, Anja Möricke, Andre Schrauder & Martin Schrappe

  2. Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany

    Martin Stanulla

Authors
  1. Gunnar Cario
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  2. Andrea Fetz
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  3. Christian Bretscher
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  4. Anja Möricke
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  5. Andre Schrauder
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  6. Martin Stanulla
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  7. Martin Schrappe
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Corresponding author

Correspondence to Gunnar Cario.

Electronic supplementary material

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Supplementary Table 1

Differentially expressed genes in the primary study set as identified by SAM analysis (DOC 91.5 kb)

Supplementary Table 2

Confirmation of selected genes by quantitative RT-PCR (DOC 30.5 KB)

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Cario, G., Fetz, A., Bretscher, C. et al. Initial leukemic gene expression profiles of patients with poor in vivo prednisone response are similar to those of blasts persisting under prednisone treatment in childhood acute lymphoblastic leukemia. Ann Hematol 87, 709 (2008). https://doi.org/10.1007/s00277-008-0504-x

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  • DOI: https://doi.org/10.1007/s00277-008-0504-x

Keywords

  • Childhood ALL
  • Prednisone resistance
  • Gene expression profiles