Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

Jonathan J. Keats, Rafael Fonseca, Marta Chesi, Roelandt Schop, Angela Baker, Wee Joo Chng, Scott Van Wier, Rodger Tiedemann, Chang Xin Shi, Michael Sebag, Esteban Braggio, Travis Henry, Yuan Xiao Zhu, Homer Fogle, Tammy Price-Troska, Gregory Ahmann, Catherine Mancini, Leslie A. Brents, Shaji Kumar, Philip GreippAngela Dispenzieri, Barb Bryant, George Mulligan, Laurakay Bruhn, Michael Barrett, Riccardo Valdez, Jeff Trent, A. Keith Stewart, John Carpten, P. Leif Bergsagel

Research output: Contribution to journalArticle

745 Scopus citations

Abstract

Activation of NF-κB 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-κB 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-κB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-κB pathway in the pathogenesis of multiple myeloma.

Original languageEnglish (US)
Pages (from-to)131-144
Number of pages14
JournalCancer cell
Volume12
Issue number2
DOIs
StatePublished - Aug 14 2007

Keywords

  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Keats, J. J., Fonseca, R., Chesi, M., Schop, R., Baker, A., Chng, W. J., Van Wier, S., Tiedemann, R., Shi, C. X., Sebag, M., Braggio, E., Henry, T., Zhu, Y. X., Fogle, H., Price-Troska, T., Ahmann, G., Mancini, C., Brents, L. A., Kumar, S., ... Bergsagel, P. L. (2007). Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma. Cancer cell, 12(2), 131-144. https://doi.org/10.1016/j.ccr.2007.07.003