The roles of TRAF3 mutation in the oncogenic progression and drug response of multiple myeloma
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REVIEW ARTICLE
The roles of TRAF3 mutation in the oncogenic progression and drug response of multiple myeloma Sultan Abda Neja1 Received: 6 June 2020 / Revised: 18 August 2020 / Accepted: 21 August 2020 / Published online: 30 August 2020 © Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare 2020
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. Keywords Multiple myeloma · NIK · NF-κb · TRAF3 · Resistance · Bortezomib
Introduction Multiple myeloma is a malignant plasma cell proliferation in the bone marrow. It is the second most prevalent hematological malignancy and accounts for about 1% of all cancers, 2% of all cancer deaths and 20% of deaths caused by hematological malignancies (Stuhmer et al. 2005; Yuregir et al. 2009). The incidence of the disease is rising in Asia, following the pattern of the aging population. Risk groups are those over 65 years of age with about 5 years of median survival time. The oncogenesis of MM is a multi-stage process preceded by monoclonal gammopathy of undetermined clinical significance (MGUS) which progresses to smoldering multiple myeloma (SMM), followed by an overt MM with the increasing rate of transformation per year and trend of * Sultan Abda Neja [email protected] 1
Faculty of Veterinary Medicine, Hawassa University, P.O.Box 05, Awassa, Ethiopia
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tumor burden across these stages (Anderson and Carrasco 2011; Fonseca et al. 2009; Kyle et al. 2007). The myeloma cells damage and weaken the bone and eventually cause anemia, lytic bone lesions that may
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