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

YN Demchenko, OK Glebov, A Zingone… - Blood, The Journal …, 2010 - ashpublications.org
YN Demchenko, OK Glebov, A Zingone, JJ Keats, PL Bergsagel, WM Kuehl
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
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.
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