Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma

Cancer Cell. 2007 Aug;12(2):115-30. doi: 10.1016/j.ccr.2007.07.004.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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

Substances

  • CD40 Antigens
  • Enzyme Inhibitors
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • NFKB1 protein, human
  • NFKB2 protein, human
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • Tumor Suppressor Proteins
  • BIRC2 protein, human
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • NF-kappa B kinase
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD