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

Leukemia. 2012 Apr;26(4):806-13. doi: 10.1038/leu.2011.265. Epub 2011 Sep 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Hodgkin Disease / drug therapy
  • Hodgkin Disease / pathology*
  • Humans
  • Ki-1 Antigen / physiology
  • Mice
  • NF-kappa B / physiology*
  • NIH 3T3 Cells
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / physiology*
  • Reed-Sternberg Cells / physiology*
  • Signal Transduction


  • Ki-1 Antigen
  • NF-kappa B
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases