Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.
Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.
Keats
Jonathan J
JJ
Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Fonseca
Rafael
R
Chesi
Marta
M
Schop
Roelandt
R
Baker
Angela
A
Chng
Wee-Joo
WJ
Van Wier
Scott
S
Tiedemann
Rodger
R
Shi
Chang-Xin
CX
Sebag
Michael
M
Braggio
Esteban
E
Henry
Travis
T
Zhu
Yuan-Xiao
YX
Fogle
Homer
H
Price-Troska
Tammy
T
Ahmann
Gregory
G
Mancini
Catherine
C
Brents
Leslie A
LA
Kumar
Shaji
S
Greipp
Philip
P
Dispenzieri
Angela
A
Bryant
Barb
B
Mulligan
George
G
Bruhn
Laurakay
L
Barrett
Michael
M
Valdez
Riccardo
R
Trent
Jeff
J
Stewart
A Keith
AK
Carpten
John
J
Bergsagel
P Leif
PL
D000256:Adenoviridae; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D010957:Plasmids; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism; 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; D051034:Inhibitor of Apoptosis Proteins; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D053303:Transmembrane Activator and CAML Interactor Protein; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C505697:LTBR protein, human; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human; C108467:TNFRSF13B protein, human; C090656:TRAF3 protein, human; C494832:BIRC3 protein, human; C409984:CYLD protein, human
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