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

Mechanisms of constitutive NF-kappa B signaling in multiple myeloma are unknown. An inhibitor of I kappa B kinase beta(IKK beta) targeting the classical NF-kappa B 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-kappa B pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappa B 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-kappa B pathway is frequent in myeloma and suggest that IKK beta inhibitors hold promise for the treatment of this disease.