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Chronic lymphocytic leukemia

Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia

Leukemia volume 33, pages 2183–2194 (2019)Cite this article

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Abstract

Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.

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Acknowledgements

We thank all patients and their physicians for CLL4 and CLL8 trial participation and donation of samples; Myriam Mendila, Nancy Valente, Stephan Zurfluh, and Jamie Wingate for their support in conception and conduct of the CLL8 trial. This work was supported by the Else Kröner-Fresenius-Stiftung (2010_Kolleg24), EC (01KT1601, FIRE CLL), BMBF (031L0076C PRECISe), and Deutsche Forschungsgemeinschaft (SFB 1074 projects B1, B2). Genetic analyses in CLL8 were supported by F. Hoffmann-La Roche.

Author contributions

B.M.C.J. designed and performed experiments, analyzed and interpreted data and wrote the manuscript; E.T., D.A.L., A.N.T.-W., and J.B. performed experiments, interpreted data and edited the manuscript; J.B. and S.R. analyzed the data and edited the manuscript; S.S. conceived study, designed experiments, interpreted data and wrote the manuscript. The remaining authors collected, analyzed, and interpreted data, and contributed to the manuscript.

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Author notes

  1. Sebastian Böttcher

    Present address: Division of Internal Medicine, Medical Clinic III, Rostock University Medical Center, Rostock, Germany

  2. Thorsten Zenz

    Present address: Division of Hematology, University Hospital Zürich, Zürich, Switzerland

Authors and Affiliations

  1. Department of Internal Medicine III, Ulm University, Ulm, Germany

    Billy Michael Chelliah Jebaraj, Eugen Tausch, Johannes Bloehdorn, Annika Scheffold, Daniel Mertens, Thorsten Zenz, Hartmut Döhner & Stephan Stilgenbauer

  2. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Dan A. Landau

  3. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, USA

    Dan A. Landau

  4. New York Genome Center, New York, NY, USA

    Dan A. Landau

  5. Department I for Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany

    Jasmin Bahlo, Sandra Robrecht, Anna-Maria Fink, Barbara Eichhorst, Kirsten Fischer & Michael Hallek

  6. Broad Institute, Cambridge, MA, USA

    Amaro N. Taylor-Weiner & Catherine J. Wu

  7. Mechanisms of Leukemogenesis, DKFZ, Heidelberg, Germany

    Daniel Mertens

  8. Department II of Internal Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany

    Sebastian Böttcher & Michael Kneba

  9. Department of Medicine I, Division of Hematology and Hemostaeology, Medical University of Vienna, Vienna, Austria

    Ulrich Jäger

  10. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Michael K. Wenger & Guenter Fingerle-Rowson

  11. Klinikum Schwabing, Academic Teaching Hospital of University of Munich, Munich, Germany

    Clemens Wendtner

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Correspondence to Stephan Stilgenbauer.

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Conflict of interest

M.K.W. and G.F.-R.: employment at F. Hoffmann-La Roche; C.W.: consultancy, membership in board of directors or advisory committees, research funding from Hoffmann-La Roche; K.F.: travel grants from Roche; M.K., U.J., M.H., and S.S.: consultancy, honoraria, and research funding from Roche. The remaining authors declare no conflict of interests.

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Jebaraj, B.M.C., Tausch, E., Landau, D.A. et al. Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia. Leukemia 33, 2183–2194 (2019). https://doi.org/10.1038/s41375-019-0446-4

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