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Letters to the Editor

Reliability of immune receptor rearrangements as genetic markers for minimal residual disease monitoring

Bone Marrow Transplantation volume 51, pages 1408–1410 (2016)Cite this article

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Detection of minimal residual disease (MRD) is a powerful prognostic tool in many hematological malignancies including ALL.1 Several groups of markers are widely used to monitor the concentration of a malignant clone including the detection of 'clonal B-cell (BCR) or T-cell (TCR) gene receptor rearrangements2 in ALL. Identification of a clonal rearrangement specific for the malignant clone, which usually constitutes from 20 to 90% in the initial bone marrow sample is a relatively straightforward task.2 Tracking this rearrangement after therapy is more tricky as the concentration of malignant cells in the sample can be very low. Recent progress in MRD detection based on quantitative real-time PCR (qPCR)3 and highthroughput sequencing (HTS)4, 5, 6 allows to detect malignant clones present at a concentration of one per 105 and even per 106 cells. Although MRD detection is claimed to be able to accurately predict the outcomes of leukemia therapy in different clinical settings, the value of this information is sometimes corrupted by false-positive and false-negative results of MRD measurement.7 One of the potential causes of false-positive results is discussed below.

Ig and TCR genes used for MRD monitoring are the most variable genes in the human organism. They are formed via the specific V(D)J recombination mechanism in each of the T or B-cell clones during maturation by joining one of each V, D and J genomic segments and inserting random nucleotides to the segment junctions. The principal theoretical diversity of TCRβ chain in humans is estimated at 1014 different variants8 and up to 1018 for BCRs heavy chains.9 As the probability of an independent recombination event in a normal cell leading to the same receptor sequence is very low, the detection of the same leukemic TCR or BCR rearrangement after therapy, at first sight, unambiguously indicates the presence of malignant cells. However, recent studies indicate that the generation probability of different TCR or BCR rearrangements can vary by several orders of magnitude. Moreover, some sequence variants could be found almost in each individual (so called public clonotypes10, 11, 12). Thus estimation of TCR and BCR rearrangement probabilities is essential for reliable MRD monitoring.

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Acknowledgements

This work was supported by Russian Ministry of Education and Science grant ID RFMEFI60414X0118. The work was carried out in part using equipment provided by the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Core Facility (CKP IBCH).

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Authors and Affiliations

  1. Department of Genetics and Postgenomic Technologies, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia

    V I Nazarov, A A Minervina, A Y Komkov, M V Pogorelyy, I V Zvyagin, D M Chudakov, Y B Lebedev & I Z Mamedov

  2. School of Computer Engineering, National Research University Higher School of Economics, Moscow, Russia

    V I Nazarov

  3. Dmitrii Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    M A Maschan & Y V Olshanskaya

  4. Department of Molecular Medicine, Pirogov Russian National Research Medical University, Moscow, Russia

    M A Maschan & D M Chudakov

  5. CEITEC MU, Masaryk University, Adaptive Immunity Lab, Brno, Czech Republic

    I V Zvyagin, D M Chudakov & I Z Mamedov

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  1. V I Nazarov
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  10. I Z Mamedov
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Correspondence to D M Chudakov or I Z Mamedov.

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Nazarov, V., Minervina, A., Komkov, A. et al. Reliability of immune receptor rearrangements as genetic markers for minimal residual disease monitoring. Bone Marrow Transplant 51, 1408–1410 (2016). https://doi.org/10.1038/bmt.2016.148

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