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Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors

Oncogene volume 34, pages 4347–4357 (2015)Cite this article

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Abstract

Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCFSkp2) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin−Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCFSkp2/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1−/− HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr–Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCFSkp2/Cks1 complex that controls CKI abundance and cancer cell proliferation.

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Acknowledgements

We thank Stephanie Schöffmann and Kerstin Behnke for excellent technical support, and the Flow Cytometry Core Facility and the Zentrum Präklinische Forschung (TU München) for expert assistance. This work was supported by the Deutsche Forschungsgemeinschaft (KE 222/7-1, OO 8/2-3, OO 8/5-1 and FOR 2033/1), the Deutsche Jose Carreras Leukämie Stiftung (R11/12 and R11/18) and the German Cancer Consortium (DKTK).

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Authors and Affiliations

  1. III. Medical Department, Technische Universität München, Munich, Germany

    V Tomiatti, R Istvánffy, E Pietschmann, S Kratzat, A Hoellein, N von Bubnoff, C Peschel, R A J Oostendorp & U Keller

  2. Institute of Pathology, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

    L Quintanilla-Fend

  3. I. Medical Department, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

    N von Bubnoff

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

    C Peschel & U Keller

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  1. V Tomiatti
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Tomiatti, V., Istvánffy, R., Pietschmann, E. et al. Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors. Oncogene 34, 4347–4357 (2015). https://doi.org/10.1038/onc.2014.364

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