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 stabi...
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| Veröffentlicht in: | Cancer cell 2007-08, Vol.12 (2), p.115 |
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| creator | Annunziata, Christina M Davis, R Eric Demchenko, Yulia Bellamy, William Gabrea, Ana Zhan, Fenghuang Lenz, Georg Hanamura, Ichiro Wright, George Xiao, Wenming Dave, Sandeep Hurt, Elaine M Tan, Bruce Zhao, Hong Stephens, Owen Santra, Madhumita Williams, David R Dang, Lenny Barlogie, Bart Shaughnessy, Jr, John D Kuehl, W Michael Staudt, Louis M |
| description | 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. |
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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. 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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. 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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.</abstract><cop>United States</cop><pmid>17692804</pmid></addata></record> |
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| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2007-08, Vol.12 (2), p.115 |
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| language | eng |
| recordid | cdi_pubmed_primary_17692804 |
| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | Baculoviral IAP Repeat-Containing 3 Protein Blotting, Western CD40 Antigens - genetics CD40 Antigens - metabolism Cells, Cultured Deubiquitinating Enzyme CYLD Enzyme Activation Enzyme Inhibitors - pharmacology Enzyme-Linked Immunosorbent Assay Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans I-kappa B Kinase - antagonists & inhibitors I-kappa B Kinase - genetics I-kappa B Kinase - metabolism Inhibitor of Apoptosis Proteins - genetics Inhibitor of Apoptosis Proteins - metabolism Multiple Myeloma - genetics Multiple Myeloma - metabolism Multiple Myeloma - pathology NF-kappa B - antagonists & inhibitors NF-kappa B - genetics NF-kappa B - metabolism NF-kappa B p50 Subunit - genetics NF-kappa B p50 Subunit - metabolism NF-kappa B p52 Subunit - genetics NF-kappa B p52 Subunit - metabolism NF-kappaB-Inducing Kinase Plasmids Polymerase Chain Reaction Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Signal Transduction TNF Receptor-Associated Factor 3 - genetics TNF Receptor-Associated Factor 3 - metabolism Transfection Translocation, Genetic Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Ubiquitin-Protein Ligases |
| title | Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma |
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