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

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Item Type:	Article
Title:	Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells
Creators Name:	Schwarzer, R., Doerken, B. and Jundt, F.
Abstract:	A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-{kappa}B (NF-{kappa}B) 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-{kappa}B 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-{kappa}B signaling, interfering with processing of the NF-{kappa}B2 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-{kappa}B 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-{kappa}B 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.
Keywords:	Notch, NF-{kappa}B, Hodgkin Lymphoma, Hodgkin and Reed-Sternberg Cells, Animals, Mice
Source:	Leukemia
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Volume:	26
Number:	4
Page Range:	806-813
Date:	April 2012
Official Publication:	https://doi.org/10.1038/leu.2011.265
PubMed:	View item in PubMed

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