title: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.
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.
authors: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Christina M
authors: CM
authors: Annunziata
authors: R Eric
authors: RE
authors: Davis
authors: Yulia
authors: Y
authors: Demchenko
authors: William
authors: W
authors: Bellamy
authors: Ana
authors: A
authors: Gabrea
authors: Fenghuang
authors: F
authors: Zhan
authors: Georg
authors: G
authors: Lenz
authors: Ichiro
authors: I
authors: Hanamura
authors: George
authors: G
authors: Wright
authors: Wenming
authors: W
authors: Xiao
authors: Sandeep
authors: S
authors: Dave
authors: Elaine M
authors: EM
authors: Hurt
authors: Bruce
authors: B
authors: Tan
authors: Hong
authors: H
authors: Zhao
authors: Owen
authors: O
authors: Stephens
authors: Madhumita
authors: M
authors: Santra
authors: David R
authors: DR
authors: Williams
authors: Lenny
authors: L
authors: Dang
authors: Bart
authors: B
authors: Barlogie
authors: John D
authors: JD
authors: Shaughnessy
authors: W Michael
authors: WM
authors: Kuehl
authors: Louis M
authors: LM
authors: Staudt
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019013:CD40 Antigens; D000074749:Deubiquitinating Enzyme CYLD; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human; C090656:TRAF3 protein, human; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; C409984:CYLD protein, human
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