Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.
Cancer Cell, 2007/8;12(2):115-30.
Annunziata CM[1], Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, Dave S, Hurt EM, Tan B, Zhao H, Stephens O, Santra M, Williams DR, Dang L, Barlogie B, Shaughnessy JD Jr, Kuehl WM, Staudt LM
Affiliations
PMID: 17692804
Impact factor: 38.585
Abstract
Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease.
MeSH terms
Baculoviral IAP Repeat-Containing 3 Protein; Blotting, Western; CD40 Antigens; Cells, Cultured; Deubiquitinating Enzyme CYLD; Enzyme Activation; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase; Inhibitor of Apoptosis Proteins; Multiple Myeloma; NF-kappa B; NF-kappa B p50 Subunit; NF-kappa B p52 Subunit; Plasmids; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Signal Transduction; TNF Receptor-Associated Factor 3; Transfection; Translocation, Genetic; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; NF-kappaB-Inducing Kinase
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