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Oncogenes, Fusion Genes and Tumor Suppressor Genes

A ‘telomere-associated secretory phenotype’ cooperates with BCR-ABL to drive malignant proliferation of leukemic cells

Leukemia volume 28, pages 2028–2039 (2014)Cite this article

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Abstract

Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL+ chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific ‘telomere-associated secretory phenotype’, comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.

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Acknowledgements

The authors thank Y Menkhaus for technical assistance and C. Verfaille (University of Minnesota, USA) for kindly providing the MSCV-BCR-ABL-eGFP and MSCV-eGFP plasmid. Sorting of eGFP-positive CML-like cells were performed by the FACS core facility at the University Hospital Hamburg-Eppendorf, Germany. This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) to MB and THB (BR-3630).

Author contributions

MB and THB designed the research and wrote the manuscript. AG and KLR provided cell samples. MB, NP, MP, DS, WH, TB and SB performed experiments and analyzed results. MC, TS, AS and SK provided data sets and did comparative analysis. CB and SB provided conceptual advice. All authors approved the final version of the manuscript and the submission.

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Authors and Affiliations

  1. Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    M Braig, N Pällmann, M Preukschas, C Bokemeyer & S Balabanov

  2. Division of Hematology, University Hospital Zürich, Zürich, Switzerland

    M Braig & S Balabanov

  3. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    D Steinemann & W Hofmann

  4. Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, Ulm, Germany

    A Gompf

  5. Institute of Clinical Chemistry, University Hospital Cologne, Cologne, Germany

    T Streichert

  6. Department of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany

    T Braunschweig

  7. Paul O’Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Scotland, UK

    M Copland

  8. Leibniz Institute of Age Research – Fritz-Lipmann Institute (FLI), Jena, Germany

    K L Rudolph

  9. Department of Hematology and Oncology, University Hospital of the RWTH Aachen, Aachen, Germany

    S Koschmieder & T H Brümmendorf

  10. Aachen Institute for Advanced Study in Computational Engineering Science (AICES), RWTH Aachen University, Aachen, Germany

    A Schuppert

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  1. M Braig
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Correspondence to T H Brümmendorf.

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Braig, M., Pällmann, N., Preukschas, M. et al. A ‘telomere-associated secretory phenotype’ cooperates with BCR-ABL to drive malignant proliferation of leukemic cells. Leukemia 28, 2028–2039 (2014). https://doi.org/10.1038/leu.2014.95

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