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Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR

Leukemia volume 16, pages 928–936 (2002)Cite this article

Abstract

Immunoglobulin gene rearrangements are used as PCR targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We investigated the occurrence of monoclonal immunoglobulin kappa-deleting element (IGK-Kde) rearrangements by Southern blotting and PCR/heteroduplex analysis at diagnosis, their stability at relapse, and their applicability in real-time quantitative PCR (RQ-PCR) analysis. In 77 selected children with precursor-B-ALL, Southern blotting detected 122 IGK-Kde rearrangements, 12 of which were derived from subclones in six patients (8%). PCR/heteroduplex analysis with BIOMED-1 Concerted Action primers identified 100 of the 110 major IGK-Kde rearrangements (91%). Comparison between diagnosis and relapse samples from 21 patients with PCR-detectable IGK-Kde rearrangements (using Southern blotting, PCR/heteroduplex analysis, and sequencing) demonstrated that 27 of the 32 rearrangements remained stable at relapse. When patients with oligoclonal IGK-Kde rearrangements were excluded, 25 of the 27 rearrangements remained stable at relapse and at least one stable rearrangement was present in 17 of the 18 patients. Subsequently, RQ-PCR analysis with allele-specific forward primers, a germline Kde TaqMan-probe, and a germline Kde reverse primer was evaluated for 18 IGK-Kde rearrangements. In 16 of the 18 targets (89%) a sensitivity of ⩽10−4 was reached. Analysis of MRD during follow-up of eight patients with IGK-Kde rearrangements showed comparable results between RQ-PCR data and classical dot-blot data. We conclude that the frequently occurring IGK-Kde rearrangements are generally detectable by PCR (90%) and are highly stable MRD-PCR targets, particularly where monoclonal rearrangements at diagnosis (95%) are concerned. Furthermore, most IGK-Kde rearrangements (90%) can be used for sensitive detection of MRD (⩽10−4) by RQ-PCR analysis.

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Acknowledgements

We thank TM van Os and WM Comans-Bitter for their assistance in the preparation of the figures. We acknowledge Daniëlle Korpershoek and Annella Boon for their accurate secretarial support. We thank Annemarie Wijkhuijs, Daniëlle Jacobs, Jacqueline van Valen, Sandra de Bruijn-Versteeg, Rob Dee, and Christa Homburg for their technical support. We thank the medical doctors of the department of Pediatrics, Sophia Children ‘s Hospital Rotterdam for the collection of samples at diagnosis and relapse. We thank the Dutch Childhood Leukemia Study Group for kindly providing some additional precursor-B-ALL cell samples. Board members of the DCLSG are PJ van Dijken, K Hählen, WA Kamps, ETh Korthof, FAE Nabben, A Postma, JA Rammeloo, GAM de Vaan, AJP Veerman, and RS Weening. This study was supported by the Dutch Cancer Foundation/Koningin Wilhelmina Fonds (grant SNWLK 2000-2268 and grant SNWLK 97–1567) and the Ank Van Vlissingen Foundation.

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Authors and Affiliations

  1. Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, Rotterdam, The Netherlands

    VHJ van der Velden, MJ Willemse & JJM van Dongen

  2. Department of Immunohematology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory of Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    CE van der Schoot

  3. Department of Pediatrics, University Hospital Rotterdam/Sophia Children's Hospital, Rotterdam, The Netherlands

    K Hählen

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

    K Hählen & ER van Wering

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van der Velden, V., Willemse, M., van der Schoot, C. et al. Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR. Leukemia 16, 928–936 (2002). https://doi.org/10.1038/sj.leu.2402475

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