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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Annunziata, CM; Davis, RE; Demchenko, Y; Bellamy, W; Gabrea, A; Zhan, F; Lenz, G; Hanamura, I; Wright, G; Xiao, W; Dave, S; Hurt, EM; Tan, B; Zhao, H; Stephens, O; Santra, M; Williams, DR; Dang, L; Barlogie, B; Shaughnessy, JD; Kuehl, WM; Staudt, LM

Published Date

  • August 2007

Published In

Volume / Issue

  • 12 / 2

Start / End Page

  • 115 - 130

PubMed ID

  • 17692804

Pubmed Central ID

  • 17692804

International Standard Serial Number (ISSN)

  • 1535-6108

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2007.07.004

Language

  • eng

Conference Location

  • United States