Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma

Cancer Cell. 2007 Aug;12(2):131-44. doi: 10.1016/j.ccr.2007.07.003.

Abstract

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.

Publication types

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

MeSH terms

  • Adenoviridae
  • Baculoviral IAP Repeat-Containing 3 Protein
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism
  • Cells, Cultured
  • Deubiquitinating Enzyme CYLD
  • Enzyme Activation
  • Fluorescent Antibody Technique
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoblotting
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Mutation / genetics*
  • 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
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nucleic Acid Hybridization
  • Plasmids
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism
  • Transfection
  • Transmembrane Activator and CAML Interactor Protein / genetics
  • Transmembrane Activator and CAML Interactor Protein / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • CD40 Antigens
  • Inhibitor of Apoptosis Proteins
  • LTBR protein, human
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • NFKB1 protein, human
  • NFKB2 protein, human
  • Neoplasm Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TNFRSF13B protein, human
  • TRAF3 protein, human
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Suppressor Proteins
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD