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

作者：Schwarzer R; Doerken B; Jundt F^*

来源：Leukemia, 2012, 26(4): 806-813.

DOI：10.1038/leu.2011.265

• Notch
• NF-kappa B
• Hodgkin lymphoma
• Hodgkin and Reed-Sternberg cells

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 c-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-kappa B 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. Leukemia (2012) 26, 806-813; doi: 10.1038/leu.2011.265; published online 27 September 2011

• 出版日期2012-4