Faculty of Science, Department of Chemistry, Princeton University, Princeton, NJ, USA.
St. Paul's Hospital and the University of British Columbia, Vancouver, BC, Canada.
Crit Rev Oncol Hematol. 2021 Jul;163:103367. doi: 10.1016/j.critrevonc.2021.103367. Epub 2021 May 29.
The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.
骨髓增生异常综合征（MDS）是一种克隆性造血干细胞疾病。MDS 患者常需要输血，导致铁过载（IOL）。IOL 增加活性氧（ROS）的产生，即氧自由基。我们回顾并说明了 IOL 诱导的 ROS 如何影响与 MDS 病理生理学相关的细胞活动。ROS 会破坏线粒体和核 DNA 中的脂质、核酸、结构蛋白、转录因子和酶。细胞后果包括代谢减少和组织及器官功能障碍。在造血干细胞（HSC）中，ROS 的后果包括糖酵解减少，使细胞从无氧代谢转变为有氧代谢，并导致 HSC 退出静止状态，从而导致 HSC 衰竭或衰老。ROS 会氧化 DNA 碱基，导致突变积累。膜氧化会改变流动性和通透性。总之，有证据表明，IOL 诱导的 ROS 改变了细胞信号通路，导致器官和造血细胞毒性，与 MDS 的不良临床结果一致。
