Jovanović Katarina K, Escure Guillaume, Demonchy Jordane, Willaume Alexandre, Van de Wyngaert Zoe, Farhat Meryem, Chauvet Paul, Facon Thierry, Quesnel Bruno, Manier Salomon
IRCL, INSERM UMR-S1172, University of Lille, Lille, France.
Department of Hematology, CHU Lille, University of Lille, Lille, France.
Front Oncol. 2019 Jan 9;8:665. doi: 10.3389/fonc.2018.00665. eCollection 2018.
Multiple Myeloma (MM) is an incurable disease characterized by a clonal evolution across the course of the diseases and multiple lines of treatment. Among genomic drivers of the disease, alterations of the tumor suppressor are associated with poor outcomes. In physiological situation, once activated by oncogenic stress or DNA damage, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. Its inactivation participates to drug resistance in MM. The frequency of alterations increases along with the progression of the disease, from 5 at diagnosis to 75% at late relapses. Multiple mechanisms of regulation lead to decreased expression of p53, such as deletion 17p, mutations, specific microRNAs overexpression, promoter methylations, and overexpression. Several therapeutic approaches aim to target the p53 pathway, either by blocking its interaction with MDM2 or by restoring the function of the altered protein. In this review, we describe the mechanism of deregulation of in MM, its role in MM progression, and the therapeutic options to interact with the pathway.
多发性骨髓瘤（MM）是一种无法治愈的疾病，其特征是在疾病进程和多线治疗过程中发生克隆进化。在该疾病的基因组驱动因素中，肿瘤抑制因子的改变与不良预后相关。在生理情况下，一旦被致癌应激或DNA损伤激活，p53会根据细胞环境诱导细胞周期停滞或凋亡。其失活参与了MM的耐药性。随着疾病进展，p53改变的频率增加，从诊断时的5%到晚期复发时的75%。多种调控机制导致p53表达降低，如17p缺失、p53突变、特定微小RNA过表达、p53启动子甲基化以及MDM2过表达。几种治疗方法旨在靶向p53途径，要么通过阻断其与MDM2的相互作用，要么通过恢复改变蛋白的功能。在本综述中，我们描述了MM中p53失调的机制、其在MM进展中的作用以及与p53途径相互作用的治疗选择。
