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Cyclin D1 mRNA as a molecular marker for minimal residual disease monitoring in patients with mantle cell lymphoma

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Abstract

Chromosomal translocation t(11;14)(q13;q32) is a characteristic molecular marker of mantle cell lymphoma (MCL) and leads to the fusion of the immunoglobulin heavy chain enhancer-promoter with the cyclin D1 gene. Both aberrant cyclin D1 expression and underlying chromosomal aberration may be used as molecular targets for monitoring minimal residual disease (MRD). The present study aims to assess the usefulness of quantitative cyclin D1 gene expression compared to the standardised but more technologically demanding DNA-based method for immunoglobulin heavy chain (IGH) or t(11;14) clone-specific gene rearrangement quantification in a cohort of bone marrow (BM) and peripheral blood (PB) samples from patients with MCL. We simultaneously evaluated DNA-MRD and cyclin D1 expression levels in 234 samples from 57 patients. We observed that both in DNA-MRD positive and negative BM/PB pairs from the same time points the expression levels of cyclin D1 are lower in PB than in BM (median 19×, BM/PB range 0.41–352). The correlation of cyclin D1 transcript levels with DNA-MRD or with flow cytometry was good only in samples with a very high infiltration. In DNA-MRD-negative BM samples, we observed a significant heterogeneity of cyclin D1 expression (in the range of more than three orders of magnitude). This is in contrast to previous reports demonstrating the usefulness of cyclin D1 for MRD monitoring that did not use DNA-based method as a reference. In PB, the specificity of cyclin D1 expression was better due to a lower physiological background. In conclusion, we show that cyclin D1 is unsuitable for MRD monitoring in BM.

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Acknowledgements

ML, MK, and RK were supported by the Grant Agency of Charles University, GAUK no. 20214; the Ministry of Health of the Czech Republic; the project for conceptual development of research organisation 00064203 (University Hospital Motol, Prague, Czech Republic), and OPPK CZ.2.16/3.1.00/24022. EF, PK, and MT were supported by AZV 17-28980A. CLIP facilities were supported by the Ministry of Education, Youth and Sports NPU I nr.LO1604, by GBP302/12/G101 and by EU-Prague project CZ.2.16/3.1.00/24505. KF, PK, and MT were supported by the Czech Ministry of Education, Youth and Sports Institutional Support for Longterm Development of Research Organizations PROGRES Q26/LF1 and PROGRES Q28/LF1.

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Author notes

  1. Milan Lokvenc and Marketa Kalinova contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Molecular Medicine, University Hospital Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

    M. Lokvenc, Marketa Kalinova & R. Kodet

  2. First Department of Medicine - Department of Haematology, Charles University General Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic

    K. Forsterova, P. Klener & M. Trneny

  3. CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

    E. Fronkova

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  1. M. Lokvenc
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  2. Marketa Kalinova
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  4. P. Klener
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Correspondence to Marketa Kalinova.

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The authors declare that they have no conflicts of interest.

Ethical approval

All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and in compliance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from each participant in this study.

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Key message

• Lack of clinical utility of cyclin D1 expression in bone marrow samples for MRD monitoring

• Better specificity of cyclin D1 expression in peripheral blood

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Lokvenc, M., Kalinova, M., Forsterova, K. et al. Cyclin D1 mRNA as a molecular marker for minimal residual disease monitoring in patients with mantle cell lymphoma. Ann Hematol 97, 467–474 (2018). https://doi.org/10.1007/s00277-017-3210-8

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  • DOI: https://doi.org/10.1007/s00277-017-3210-8

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