文章：

理解多发性骨髓瘤中的DNA损伤应答与DNA修复机制

Understanding DNA Damage Response and DNA Repair in Multiple Myeloma

原文发布日期：17 August 2023

DOI: 10.3390/cancers15164155

类型: Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.

摘要翻译： 

多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征表现为多种遗传异常，包括染色体易位、基因组缺失与扩增以及点突变。在MM中，DNA损伤应答（DDR）与DNA修复机制发生改变，从而促进肿瘤发生发展、疾病进展及治疗耐药。由于共济失调毛细血管扩张突变（ATM）基因功能丧失或突变，以及肿瘤蛋白p53（TP53）和肿瘤蛋白p73（TP73）的缺失、突变或表达下调，受损DNA很少引发细胞凋亡反应。此外，DNA修复机制或过度活跃或存在缺陷，以实现损伤的快速修复或允许细胞存活。用于治疗MM患者的药物可通过直接作用（如美法仑诱导的单加合物）或通过蛋白酶体抑制剂（如硼替佐米）产生活性氧（ROS）而引起DNA损伤。本综述将阐述正常组织中DDR与DNA修复的机制，探讨这些通路对MM疾病进展及其他表型的促进作用，并分析MM患者的潜在治疗策略。

原文链接：

Understanding DNA Damage Response and DNA Repair in Multiple Myeloma