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Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma

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Abstract

Resistance to cell death is the major cause of chemotherapy failure in most kinds of cancers, including Burkitt lymphoma (BL). When analyzing therapy resistance in Burkitt lymphoma (BL), we discovered a link between apoptosis resistance and ploidy control. We therefore studied systematically a panel of 15 BL lines for apoptosis induction upon treatment with microtubule inhibitors and compared three types of microtubule toxins, i.e., paclitaxel, nocodazole and vincristine. We found an inverse relationship between apoptosis sensitivity and ploidy control. Thus, cells resistant to paclitaxel- or nocodazole-induced apoptosis underwent mitotic catastrophe and developed polyploidy (>4N). Mechanistically, apoptosis resistance was linked to failure of caspase activation, which was most pronounced in cells lacking the pro-apoptotic multidomain Bcl-2 homologs Bax and Bak. Pharmacological caspase inhibition promoted polyploidy upon exposure to paclitaxel and nocodazole supporting the relationship between resistance to apoptosis and polyploidization. Of note, vincristine induced persistent mitotic arrest but no loss of ploidy control. Considering targets to facilitate Bax/Bak-independent cell death and to avoid drug-induced mitotic catastrophe and consecutive mitotic catastrophe should be of great importance to overcome therapy resistance and therapy-related events that result in ploidy changes and tumor progression.

Key message

  • Inverse relation of apoptosis and polyploidy induction by paclitaxel or nocodazole in BL.

  • Resistant cells undergo mitotic catastrophe and develop polyploidy.

  • Lack of Bax/Bak confers resistance and leads to induction of polyploidy in BL.

  • Intact apoptosis response protects from polyploidy as a result of mitotic catastrophe.

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Acknowledgments

This work was supported by grants from the Deutsche José Carreras Leukämiestiftung e.V. to P.T.D. and the Deutsche Krebshilfe-funded MMML (molecular mechanisms in malignant lymphoma) consortium to C.P. and P.T.D. We would like to thank Dr. Georg Bornkamm, Institute of Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, München, Germany, and Dr. Marina Gutierrez, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia, for the kind gift of Burkitt lymphoma cell lines and Dr. Paul Ekert, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Australia, for providing us with murine FDM cells of various genetic backgrounds.

Conflict of interest

All authors have read and approved the final version of the manuscript. None of the authors has any type of financial interest to disclose.

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Authors and Affiliations

  1. Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Virchow Klinikum, Humboldt University, 13353, Berlin, Germany

    Bernhard Gillissen, Anja Richter, Antje Richter, Tim Overkamp, Anja Müller & Peter T. Daniel

  2. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Bernhard Gillissen, Anja Richter & Peter T. Daniel

  3. Clinical and Molecular Oncology, University Medical Center Charité and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin-Buch, Germany

    Cindrilla Chumduri, Ana Milojkovic & Peter T. Daniel

  4. Department of Internal Medicine II, University Hospital Schleswig-Holstein, Christian-Albrechts University, Campus Kiel, 24116, Kiel, Germany

    Christiane Pott

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  1. Cindrilla Chumduri
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  2. Bernhard Gillissen
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  3. Anja Richter
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  9. Peter T. Daniel
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Correspondence to Peter T. Daniel.

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Cindrilla Chumduri and Bernhard Gillissen contributed equally to this work.

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Chumduri, C., Gillissen, B., Richter, A. et al. Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma. J Mol Med 93, 559–572 (2015). https://doi.org/10.1007/s00109-014-1242-2

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  • DOI: https://doi.org/10.1007/s00109-014-1242-2

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