The roles of TRAF3 mutation in the oncogenic progression and drug response of multiple myeloma

Abstract

Multiple myeloma (MM) is a malignant plasma cell proliferating in the bone marrow. Oncogenesis of MM is a multi-stage cytogenetic event. Among these, aberrant activation of the non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is critical for the oncogenic progression of MM. Tumor necrosis factor receptor‐associated factor 3 (TRAF3) mutation is among the most common tumor suppressor mutations in MM that allows constitutive activation of the non-canonical NF-кB pathway, thereby enhancing de novo survival of MM cells. Although there are some promising developments on current therapeutic regimens for MM patients that target such NF-кB signature, drug resistance perhaps remains a major concern. So far, TRAF3 mutation has been reported to modulate proteasome inhibitor response of MM. Mechanistically, concomitant to TRAF3 mutation-associated NIK stability that leads to the pathway activation, it has been reported that bortezomib treatment also causes a drastic increase in the level of NIK that causes pathway cross talk activating the canonical pathway, thereby triggering an acquired proteasome inhibitor resistance (PIR) pathway. Concomitantly targeting such NIK-driven acquired PIR or else targeting NIK than TRAF3 mutation and associated phenotype is likely to be the better option and thus remains to be elucidated. Hence, this review explains the roles of TRAF3-mutation-associated NF-кB pathway activation in the oncogenic progression and drug response of MM.