Classical and/or alternative NF-κB pathway activation in multiple myeloma

Yulia N. Demchenko, Oleg K. Glebov, Adriana Zingone, Jonathan J. Keats, Peter Leif Bergsagel, W. Michael Kuehl

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184 Scopus citations

Abstract

Mutations involving the nuclear factor-κB (NF-κB) pathway are present in at least 17% of multiple myeloma (MM) tumors and 40% of MM cell lines (MMCLs). These mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NF-κB. Studies on a panel of 51 MMCLs provide some clarification of the mechanisms through which these mutations act and the significance of classical versus alternative activation of NF-κB. First, only one mutation (NFKB2) selectively activates the alternative pathway, whereas several mutations (CYLD, NFKB1, and TACI) selectively activate the classical pathway. However, most mutations affecting NF-κB-inducing kinase (NIK) levels (NIK, TRAF2, TRAF3, cIAP1&2, and CD40) activate the alternative but often both pathways. Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteasomal degradation of NIK in MM. Third, using transfection to selectively activate the classical or alternative NF-κB pathways, we show virtually identical changes in gene expression in one MMCL, whereas the changes are similar albeit nonidentical in a second MMCL. Our results suggest that MM tumors can achieve increased autonomy from the bone marrow microenvironment by mutations that activate either NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)3541-3552
Number of pages12
JournalBlood
Volume115
Issue number17
DOIs
StatePublished - Apr 29 2010

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Demchenko, Y. N., Glebov, O. K., Zingone, A., Keats, J. J., Bergsagel, P. L., & Michael Kuehl, W. (2010). Classical and/or alternative NF-κB pathway activation in multiple myeloma. Blood, 115(17), 3541-3552. https://doi.org/10.1182/blood-2009-09-243535