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Nat Commun. 2017 Nov 22;8(1):1697. doi: 10.1038/s41467-017-01850-4.

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

Author information

1
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, A-6020, Innsbruck, Austria.
2
Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80, A-6020, Innsbruck, Austria.
3
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, A-6020, Innsbruck, Austria. andreas.villunger@i-med.ac.at.
4
Tyrolean Cancer Research Institute, Innrain 66, A-6020, Innsbruck, Austria. andreas.villunger@i-med.ac.at.

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.

PMID:
29167438
PMCID:
PMC5700047
DOI:
10.1038/s41467-017-01850-4
[Indexed for MEDLINE]
Free PMC Article

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