Kontandreopoulou Christina-Nefeli, Kalopisis Konstantinos, Viniou Nora-Athina, Diamantopoulos Panagiotis
First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Front Oncol. 2022 Oct 20;12:989483. doi: 10.3389/fonc.2022.989483. eCollection 2022.
Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.
基因组不稳定、微环境异常和体细胞突变促成了骨髓增生异常综合征的表型以及向急性髓系白血病转化的风险。参与RNA剪接、DNA甲基化、组蛋白修饰、黏连蛋白复合体、转录、DNA损伤反应通路、信号转导及其他通路的基因构成了骨髓增生异常综合征中反复出现的突变靶点。RNA剪接和DNA甲基化突变似乎发生得较早，在超过50%的骨髓增生异常综合征患者中被报道为驱动突变。对骨髓增生异常综合征分子格局的深入了解已带来更好的疾病和风险分类，从而带来新的治疗机会。基于这些发现，新型药物目前正处于临床前和临床开发阶段，预计在未来几年将改善骨髓增生异常综合征患者的临床结局。本综述全面更新了正常基因功能以及突变在骨髓增生异常综合征的发病机制、失调、诊断和预后中的影响，重点关注骨髓增生异常综合征遗传基础的最新进展及其临床相关性，以及最新的靶向治疗方法，包括用于骨髓增生异常综合征的研究性药物和已获批药物。
