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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Cell Activating Factor / genetics
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B-Cell Activating Factor / metabolism
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B-Cell Activation Factor Receptor / antagonists & inhibitors
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B-Cell Activation Factor Receptor / genetics
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B-Cell Activation Factor Receptor / metabolism*
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Baculoviral IAP Repeat-Containing 3 Protein
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Blotting, Western
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Cell Nucleus / metabolism
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Cell Proliferation
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Humans
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Immunoenzyme Techniques
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Immunoprecipitation
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism*
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Lymphoma, Large B-Cell, Diffuse / pathology
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NF-KappaB Inhibitor alpha
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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NF-kappaB-Inducing Kinase
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Phosphorylation
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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TNF Receptor-Associated Factor 2 / antagonists & inhibitors
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TNF Receptor-Associated Factor 2 / genetics
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TNF Receptor-Associated Factor 2 / metabolism
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TNF Receptor-Associated Factor 3 / antagonists & inhibitors
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism
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Tissue Array Analysis
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Ubiquitin-Protein Ligases
Substances
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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I-kappa B Proteins
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Inhibitor of Apoptosis Proteins
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NF-kappa B
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NFKBIA protein, human
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RNA, Messenger
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RNA, Small Interfering
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 3
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TNFSF13B protein, human
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TRAF3 protein, human
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NF-KappaB Inhibitor alpha
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases