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Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis

Author

Listed:
  • Fabian Schuler

    (Biocenter, Medical University of Innsbruck)

  • Johannes G. Weiss

    (Biocenter, Medical University of Innsbruck)

  • Silke E. Lindner

    (Biocenter, Medical University of Innsbruck)

  • Michael Lohmüller

    (Biocenter, Medical University of Innsbruck)

  • Sebastian Herzog

    (Biocenter, Medical University of Innsbruck)

  • Simon F. Spiegl

    (Biocenter, Medical University of Innsbruck)

  • Philipp Menke

    (Biocenter, Medical University of Innsbruck)

  • Stephan Geley

    (Biocenter, Medical University of Innsbruck)

  • Verena Labi

    (Biocenter, Medical University of Innsbruck)

  • Andreas Villunger

    (Biocenter, Medical University of Innsbruck
    Tyrolean Cancer Research Institute)

Abstract

Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice. Moreover, total ablation of Chk1 in B-cells arrests their development at the pro-B cell stage, a block that, surprisingly, cannot be overcome by inhibition of mitochondrial apoptosis, as cell cycle arrest is initiated as an alternative fate to limit the spread of damaged DNA. Our findings define CHK1 as essential in B-cell development and potent target to treat blood cancer.

Suggested Citation

  • Fabian Schuler & Johannes G. Weiss & Silke E. Lindner & Michael Lohmüller & Sebastian Herzog & Simon F. Spiegl & Philipp Menke & Stephan Geley & Verena Labi & Andreas Villunger, 2017. "Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01850-4
    DOI: 10.1038/s41467-017-01850-4
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    Cited by:

    1. Marina A. Schapfl & Gina M. LoMastro & Vincent Z. Braun & Maretoshi Hirai & Michelle S. Levine & Eva Kiermaier & Verena Labi & Andrew J. Holland & Andreas Villunger, 2024. "Centrioles are frequently amplified in early B cell development but dispensable for humoral immunity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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