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Chronic lymphocytic leukemia

Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling

Leukemia volume 32, pages 72–82 (2018)Cite this article

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Abstract

The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-κB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-κB and tumor suppressor gene CYLD regulates the pool of CD5+ B cells through sustained canonical NF-κB signaling. Reinforced canonical NF-κB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5+ B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-κB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-κB-driven clonal CD5+ B-cell expansion and ultimately CLL-like disease.

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Acknowledgements

We thank Marc Schmidt-Supprian for excellent scientific discussions, Petra Adams-Quack and Elena Zurkowski for technical help. We thank Linda Koch and Florian Kurschus for critically proof reading the manuscript. This project was supported by the DFG: HO 4440/1-02.

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Authors and Affiliations

  1. Institute for Molecular Medicine, University Medical Centre of the Johannes Gutenberg-University of Mainz, Mainz, Germany

    M Hahn, C A Luttenberger, S Klebow, S Reißig, A Waisman & N Hövelmeyer

  2. Department of Infection and Immunity, Luxembourg Institute of Health, Strassen, Luxembourg

    J-P Bürckert & C P Muller

  3. Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre of the Johannes Gutenberg-University of Mainz, Mainz, Germany

    M Hess

  4. Max Planck Institute for Metabolism Research, CECAD, CMMC, Institute for Genetics, Cologne, Germany

    M Al-Maarri, M Vogt & F T Wunderlich

  5. Department I of Internal Medicine, CMMC, CECAD, University of Cologne, Cologne, Germany

    M Hallek & C P Pallasch

  6. Life Science Research Unit (LSRU), University of Luxembourg, Esch-sur-Alzette, Luxembourg

    A Wienecke-Baldacchino

  7. Institute of Laboratory Animal Science, University of Zürich, Zürich, Switzerland

    T Buch

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Hahn, M., Bürckert, JP., Luttenberger, C. et al. Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling. Leukemia 32, 72–82 (2018). https://doi.org/10.1038/leu.2017.168

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