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Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma: a study of younger patients from the MCL2 and MCL3 clinical trials

Leukemia volume 36, pages 177–188 (2022)Cite this article

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A Correction to this article was published on 18 February 2022

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Abstract

Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.

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Fig. 1: CircRNAs are widely expressed in MCL.
Fig. 2: CircRNA expression is inversely correlated with the cell proliferation marker Ki67.
Fig. 3: CircSCORE is significantly associated with outcome in MCL.
Fig. 4: CircSCORE is independently associated with outcome in the validation cohort MCL3.
Fig. 5: CircSCORE retains prognostic impact in a combined cohort of patients with TP53wt MCL.

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Acknowledgements

The authors would like to thank staff members of all contributing departments of the MCL2 and MCL3 clinical trials, and we are grateful to all patients who participated. We thank Morten Venø for his help processing the RNA-seq data and MD Eileen Wedge for proofreading the manuscript. This work was supported by grants from Rigshospitalets Research foundation, The Novo Nordisk Foundation (NNF17OC0029596), The Lundbeck Foundation (R307-2018-3433), “Mindegaard Donationen, Rigshospitalet” and “Sejer Persson & Lis Klüver Persson’s fund”. K.G is funded by a center grant from The Danish Cancer Society (Danish Research Center for Precision Medicine in Blood Cancer; grant 223-A13071-18-S68), from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852) and from Greater Copenhagen Health Science Partners (Clinical Academic Group in Blood Cancers).

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  1. These authors contributed equally: Lasse S. Kristensen, Kirsten Grønbæk

Authors and Affiliations

  1. Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Mette Dahl, Simon Husby, Christian W. Eskelund, Christophe Côme, Christian H. Geisler & Kirsten Grønbæk

  2. Biotech Research and Innovation Centre, Copenhagen University, Copenhagen, Denmark

    Mette Dahl, Simon Husby, Christian W. Eskelund, Christophe Côme & Kirsten Grønbæk

  3. Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Mette Dahl, Simon Husby, Christophe Côme & Kirsten Grønbæk

  4. Department of Molecular Medicine (MOMA), Aarhus University, Aarhus, Denmark

    Søren Besenbacher

  5. Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark

    Søren Fjelstrup & Jørgen Kjems

  6. Department of Immunotechnology, Lund University, Lund, Sweden

    Sara Ek

  7. Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway

    Arne Kolstad

  8. Department of Hematology, Helsinki University Hospital, Helsinki, Finland

    Riikka Räty

  9. Division of Oncology, Lund University, Lund, Sweden

    Mats Jerkeman

  10. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Jørgen Kjems

  11. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Lasse S. Kristensen

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Dahl, M., Husby, S., Eskelund, C.W. et al. Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma: a study of younger patients from the MCL2 and MCL3 clinical trials. Leukemia 36, 177–188 (2022). https://doi.org/10.1038/s41375-021-01311-4

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