Classical and/or alternative NF-kappaB pathway activation in multiple myeloma.
Mutations involving the nuclear factor-kappaB (NF-kappaB) pathway are present in at least 17% of multiple myeloma (MM) tumors and 40% of MM cell lines (MMCLs). These mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NF-kappaB. Studies on a panel of 51 MMCLs provide some clarification of the mechanisms through which these mutations act and the significance of classical versus alternative activation of NF-kappaB. First, only one mutation (NFKB2) selectively activates the alternative pathway, whereas several mutations (CYLD, NFKB1, and TACI) selectively activate the classical pathway. However, most mutations affecting NF-kappaB-inducing kinase (NIK) levels (NIK, TRAF2, TRAF3, cIAP1&2, and CD40) activate the alternative but often both pathways. Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteasomal degradation of NIK in MM. Third, using transfection to selectively activate the classical or alternative NF-kappaB pathways, we show virtually identical changes in gene expression in one MMCL, whereas the changes are similar albeit nonidentical in a second MMCL. Our results suggest that MM tumors can achieve increased autonomy from the bone marrow microenvironment by mutations that activate either NF-kappaB pathway.
Demchenko
Yulia N
YN
Genetics Branch, National Cancer Institute, Bethesda, MD, USA.
Glebov
Oleg K
OK
Zingone
Adriana
A
Keats
Jonathan J
JJ
Bergsagel
P Leif
PL
Kuehl
W Michael
WM
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; 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; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D046988:Proteasome Endopeptidase Complex; 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; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human; C108467:TNFRSF13B protein, human; C090656:TRAF3 protein, human; C494832:BIRC3 protein, human; C409984:CYLD protein, human