Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways

Blood. 2011 Jan 6;117(1):200-10. doi: 10.1182/blood-2010-06-290437. Epub 2010 Oct 1.

Abstract

Aberrant nuclear factor κB (NF-κB) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-κB signaling pathway has been studied in some detail, activation of the alternative NF-κB pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-κB pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-κB-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-κB pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, IκBα phosphorylation, and NF-κB p100 processing, thereby resulting in continuous activation of both NF-κB pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-κB activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / metabolism
  • B-Cell Activation Factor Receptor / antagonists & inhibitors
  • B-Cell Activation Factor Receptor / genetics
  • B-Cell Activation Factor Receptor / metabolism*
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappaB-Inducing Kinase
  • Phosphorylation
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism
  • Tissue Array Analysis
  • Ubiquitin-Protein Ligases

Substances

  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • I-kappa B Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TNFSF13B protein, human
  • TRAF3 protein, human
  • NF-KappaB Inhibitor alpha
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases