Understanding DNA Damage Response and DNA Repair in Multiple Myeloma.
Understanding DNA Damage Response and DNA Repair in Multiple Myeloma.
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DOI：
10.3390/cancers15164155
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发表时间：
2023-08-17
期刊：
影响因子：
5.2
通讯作者：
Cottini F
中科院分区：
文献类型：
--
作者：
Petrilla C;Galloway J;Kudalkar R;Ismael A;Cottini F
多发性骨髓瘤（MM）是一种以异常DNA损伤反应（DDR）为特征的恶性浆细胞疾病。随着时间的推移，MM细胞通过基因突变或染色体畸变（包括DDR和DNA修复基因的变化）进行适应。增加DNA修复和避免DNA损伤诱导的细胞死亡促进肿瘤形成、进展和对治疗的抗性。由于广泛的DDR和DNA修复机制，DDR是一个难以捉摸的目标。目前，MM患者常用蛋白酶体抑制剂和烷化剂等治疗方法。这些治疗方法以不同的方式影响DDR和DNA修复途径。随着更多的研究进行，针对DDR机制可能会出现新的治疗方法，如本综述所述。多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征在于几种遗传异常，包括染色体易位、基因组缺失和获得以及点突变。DNA损伤反应（DDR）和DNA修复机制在MM中发生改变，以允许肿瘤发生、进展和对治疗产生抗性。损伤的DNA很少诱导凋亡反应，因为存在共济失调-毛细血管扩张突变（ATM）功能丧失或突变，以及肿瘤蛋白p53（TP 53）和肿瘤蛋白p73（TP 73）的缺失、突变或下调。此外，DNA修复机制要么是过度活跃的，要么是有缺陷的，以允许快速纠正损伤或允许生存。用于治疗MM患者的药物可以通过直接作用（美法仑诱导的单加合物）或蛋白酶体抑制剂（例如硼替佐米）产生活性氧簇（ROS）来诱导DNA损伤。在这篇综述中，我们将描述DDR和DNA修复在正常组织中的机制，这些途径对MM疾病进展和其他表型的贡献，以及MM患者的潜在治疗机会。
Multiple myeloma (MM), a malignant plasma cell disorder, is characterized by abnormal DNA damage response (DDR). MM cells adapt over time via gene mutations or chromosomal aberrations, including changes to DDR and DNA repair genes. Increased DNA repair and avoidance of DNA-damaged induced cellular death promote tumor formation, progression, and resistance to treatments. Because of the wide array of DDR and DNA repair mechanisms, DDR is an elusive target. Currently, treatments such as proteasome inhibitors and alkylating agents are commonly used in patients with MM. These treatments affect DDR and DNA repair pathways in different ways. As more studies are conducted, targeting DDR mechanisms might emerge as new treatments, as described in this review. 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.
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