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.
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.
Pham
Lan V
LV
Department of Hematopathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Fu
Lingchen
L
Tamayo
Archito T
AT
Bueso-Ramos
Carlos
C
Drakos
Elias
E
Vega
Francisco
F
Medeiros
L Jeffrey
LJ
Ford
Richard J
RJ
D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C505719:TNFSF13B protein, human; C090656:TRAF3 protein, human; C494832:BIRC3 protein, human