Journal of Molecular Medicine

, Volume 93, Issue 5, pp 559–572 | Cite as

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

  • Cindrilla Chumduri
  • Bernhard Gillissen
  • Anja Richter
  • Antje Richter
  • Ana Milojkovic
  • Tim Overkamp
  • Anja Müller
  • Christiane Pott
  • Peter T. DanielEmail author
Original Article


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.


Mitotic catastrophe Aneuploidy Apoptosis Bax Bak Caspase 



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.

Supplementary material

109_2014_1242_MOESM1_ESM.pdf (523 kb)
ESM 1 (PDF 522 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Cindrilla Chumduri
    • 3
  • Bernhard Gillissen
    • 1
    • 2
  • Anja Richter
    • 1
    • 2
  • Antje Richter
    • 1
  • Ana Milojkovic
    • 3
  • Tim Overkamp
    • 1
  • Anja Müller
    • 1
  • Christiane Pott
    • 4
  • Peter T. Daniel
    • 1
    • 2
    • 3
    Email author
  1. 1.Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Virchow KlinikumHumboldt UniversityBerlinGermany
  2. 2.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Clinical and Molecular OncologyUniversity Medical Center Charité and Max-Delbrück-Center for Molecular MedicineBerlin-BuchGermany
  4. 4.Department of Internal Medicine II, University Hospital Schleswig-HolsteinChristian-Albrechts UniversityKielGermany

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