Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.
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.
Annunziata
Christina M
CM
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Davis
R Eric
RE
Demchenko
Yulia
Y
Bellamy
William
W
Gabrea
Ana
A
Zhan
Fenghuang
F
Lenz
Georg
G
Hanamura
Ichiro
I
Wright
George
G
Xiao
Wenming
W
Dave
Sandeep
S
Hurt
Elaine M
EM
Tan
Bruce
B
Zhao
Hong
H
Stephens
Owen
O
Santra
Madhumita
M
Williams
David R
DR
Dang
Lenny
L
Barlogie
Bart
B
Shaughnessy
John D
JD
Kuehl
W Michael
WM
Staudt
Louis M
LM
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
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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