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Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program

Leukemia volume 17, pages 2318–2357 (2003)Cite this article

Abstract

Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35–45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer (EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n=278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

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Acknowledgements

This work has been supported by the SANCO European Commission (no. SI2.129294 (99CVF2-016) and Applied Biosystems (Foster City, CA, USA). Additional support was given by national grants: ARC no. 5484, Ligue Contre le Cancer, Dutch Cancer Society/Koningin Wilhelmina Fonds (Grant SNWLK 2000-2268), Leukaemia Research Fund of Great Britain and Special Trustees of Guy's Hospital (DG); Fondos de Investigación de la Seguridad Social (00/1079), Beca del Instituto de Salut Carlos III (99/4230) and Fondos Feder (AC G7); Associazione Italiana per la Ricerca sul Cancro (AIRC), MURST and Fondazione M Tettamanti (GC), CNR PF Biotecnologie (Rome), MIUR (Rome), AIL (Rome), Regione Campania and Swedish Cancer Society.

We like to thank W Mayser for his logistic support during meetings, K Livak for useful discussions and C Marcou for secretarial assistance.

Author information

Author notes

  1. J Gabert and E Beillard: First co-authors

  2. J Gabert: Present affiliation: Department of Biochemistry & Molecular Biology, Hôpital Universitaire Nord, ERT MEIDIA, IFR Jean Roche, Université de la Méditerranée, Marseille, France

  3. J Gabert: Consultant for Ipsogen

  4. G Barbany: Present affiliation: Department of Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden

Authors and Affiliations

  1. Department of Hematology Biology, Institut Paoli Calmettes, France

    J Gabert & E Beillard

  2. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    V H J van der Velden & J J M van Dongen

  3. Applied Biosystems, Foster City, CA, USA

    W Bi

  4. Department of Haematology, Division of Medical and Molecular Genetics, Guy's, King's & St Thomas’ School of Medicine, University College London Hospitals, London, UK

    D Grimwade

  5. Department of Immuno-haematology, Aarhus University Hospital, Aarhus, Denmark

    N Pallisgaard

  6. Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden

    G Barbany

  7. Pediatric Clinic, University of Milan Bicocca, San Gerardo Hospital, Monza, Italy

    G Cazzaniga

  8. Central Laboratory of Hematology and INSERM U462, Hôpital Saint Louis, Paris, France

    J M Cayuela

  9. Department of Genetic Biochemistry, Hôpital Robert Debré, Paris, France

    H Cavé

  10. Department of CEINGE & Department of Biochemistry & Medical Biotechnology, University Hospital ‘Federico II’, Naples, Italy

    F Pane

  11. Department of Haematology, University Hospital, Leuven, Belgium

    J L E Aerts

  12. Clinical and Biological Science, University of Turin, Ospedale San Luigi Gonzaga, Orbassano-Torino, Italy

    D De Micheli & G Saglio

  13. Department of Medical Information, University Hôpital Sainte Marguerite/Biostatistics Laboratory Timone, Université de la Méditerranée, Marseille, France

    X Thirion & V Pradel

  14. Department of Hematology, Hospital Clínico Universitario, Salamanca, Spain

    M González

  15. Biogenetics Laboratory, Children's University Hospital, Giessen, Germany

    S Viehmann

  16. Department of Hematology, Karolinska, Stockholm, Sweden

    M Malec

Authors
  1. J Gabert
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  2. E Beillard
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  3. V H J van der Velden
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  4. W Bi
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  5. D Grimwade
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  6. N Pallisgaard
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  7. G Barbany
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  8. G Cazzaniga
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  9. J M Cayuela
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  10. H Cavé
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  11. F Pane
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  12. J L E Aerts
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  13. D De Micheli
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  14. X Thirion
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  15. V Pradel
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  16. M González
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  17. S Viehmann
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  18. M Malec
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  19. G Saglio
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  20. J J M van Dongen
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Corresponding author

Correspondence to J Gabert.

Additional information

The EAC network was composed of the following additional laboratories: (please see Table 36 below)

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

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Gabert, J., Beillard, E., van der Velden, V. et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program. Leukemia 17, 2318–2357 (2003). https://doi.org/10.1038/sj.leu.2403135

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  • DOI: https://doi.org/10.1038/sj.leu.2403135

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