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Lymphoma

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Leukemia volume 26, pages 806–813 (2012)Cite this article

Abstract

A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-κB (NF-κB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed–Sternberg (HRS) cells. Despite abundant evidence for a complex context-dependent cross talk between Notch and NF-κB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the γ-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-κB signaling, interfering with processing of the NF-κB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-κB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-κB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-κB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (DFG, TRR54, TPB6 to FJ and BD) and the Wilhelm-Sander Stiftung (2006.069.2). We thank Katharina Pardon and Alexander Haake for excellent technical assistance.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Charité, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany

    R Schwarzer, B Dörken & F Jundt

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    B Dörken & F Jundt

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  1. R Schwarzer
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  2. B Dörken
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Correspondence to F Jundt.

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Schwarzer, R., Dörken, B. & Jundt, F. Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells. Leukemia 26, 806–813 (2012). https://doi.org/10.1038/leu.2011.265

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