Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma

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