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Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia

Leukemia volume 18, pages 709–719 (2004)Cite this article

Abstract

Current MRD studies in T-cell acute lymphoblastic leukemia (T-ALL) mainly use T-cell receptor gamma, delta and SIL-TAL1 gene rearrangements as MRD-PCR targets. However, low frequency or limited diversity of these markers restricts the number of evaluable patients, particularly because two markers are recommended for MRD monitoring. Hence, we developed a new strategy implementing the TCR beta (TCRB) locus for MRD quantification. The frequency and characteristics of complete and incomplete TCRB rearrangements were investigated in 53 childhood and 100 adult T-ALL patients using the BIOMED-2 multiplex PCR assay. Clonal rearrangements were identified in 92% both childhood and adult T-ALL (Vβ–Dβ–Jβ rearrangements in 80%, Dβ–Jβ rearrangements in 53%). Comparative sequence analysis of 203 TCRB recombinations revealed preferential usage of the ‘end-stage’ segment Jβ2.7 in childhood T-ALL (27%), whereas Jβ2.3 was most frequently involved in adult T-ALL (24%). In complete rearrangements, three downstream Vβ segments (19–1/20–1/21–1) were preferentially used. Subsequently, a TCRB real-time quantitative PCR assay to quantify MRD with 13 germline Jβ primer/probe combinations and allele-specific oligonucleotides was developed and applied to 60 clonal TCRB rearrangements. The assay allowed the detection of one leukemic cell within at least 104 polyclonal cells in 93% of cases and will be of high value for future MRD studies.

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Acknowledgements

We gratefully acknowledge Petra Chall, Petra Neumann, Frauke Hemken and Heidrun Seppelt for their technical assistance, Margot Ulrich for preparation of the figures, Sabine Hug and Regina Reutzel for providing clinical data and the German Multicenter ALL Study Group and the Dutch Childhood Leukemia Group for kindly providing the ALL samples. This work was supported by the Wilhelm Sander-Stiftung (Grant 2001.074.1), the German Compentence Network ‘Akute und Chronische Leukämien’ and by the Dutch Cancer Society/Koningin Wilhelmina Fonds (Grant SNWLK 97-1567 and Grant SNWLK 2000-2268).

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Authors and Affiliations

  1. Medical Clinic II, University of Kiel, Germany

    M Brüggemann, T Raff, J Droese, M Ritgen, C Pott & M Kneba

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

    V H J van der Velden, A J Wijkhuijs & J J M van Dongen

  3. Department of Hematology, Medical Clinic III, University of Frankfurt, Germany

    N Gökbuget & D Hoelzer

  4. Dutch Childhood Leukemia Study Group, The Hague, The Netherlands

    E R van Wering

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  1. M Brüggemann
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Correspondence to M Brüggemann.

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Brüggemann, M., van der Velden, V., Raff, T. et al. Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia. Leukemia 18, 709–719 (2004). https://doi.org/10.1038/sj.leu.2403263

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