The bone marrow microenvironment plays important roles in the progression of the myelodysplastic syndrome (MDS). The higher incidence of ASXL1 and TET2 gene mutations in our iron overload (IO) MDS patients suggests that IO may be involved in the pathogenesis of MDS. The effects of IO damaging bone marrow mesenchymal stromal cells (MSCs) from higher-risk MDS patients were investigated. In our study, IO decreased the quantity and weakened the abilities of proliferation and differentiation of MSCs, and it inhibited the gene expressions of VEGFA, CXCL12, and TGF-β1 in MSCs regulating hematopoiesis. The increased level of reactive oxygen species (ROS) in MSCs caused by IO might be inducing apoptosis by activating caspase3 signals and involving in MDS progression by activating β-catenin signals. The damages of MSCs caused by IO could be partially reversed by an antioxidant or an iron chelator. Furthermore, the MSCs in IO MDS/AML patients had increased levels of ROS and apoptosis, and the expressions of caspase3 and β-catenin were increased even further. In conclusion, IO affects gene stability in higher-risk MDS patients and impairs MSCs by inducing ROS-related apoptosis and activating the Wnt/β-catenin signaling pathway, which could be partially reversed by an antioxidant or an iron chelator.

中文翻译：

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铁超载通过调节ROS相关的Wnt /β-Catenin途径损害高危MDS患者的骨髓间质基质细胞

骨髓微环境在骨髓增生异常综合症（MDS）的进展中起重要作用。铁超负荷（IO）MDS患者中ASXL1和TET2基因突变的发生率较高，表明IO可能与MDS的发病机制有关。研究了高危MDS患者的IO损伤性骨髓间充质基质细胞（MSC）的作用。在我们的研究中，IO减少了MSCs的数量，削弱了它们的增殖和分化能力，并抑制了调节造血功能的MSCs中VEGFA，CXCL12和TGF- β1的基因表达。IO引起的MSC中活性氧（ROS）水平升高可能是通过激活caspase3信号诱导凋亡，并通过激活β参与MDS进程-catenin信号。IO引起的MSC损伤可以通过抗氧化剂或铁螯合剂部分逆转。此外，IO MDS / AML患者中的MSC的ROS水平升高和凋亡，并且caspase3和β -catenin的表达进一步增加。总之，IO通过诱导ROS相关凋亡和激活Wnt / β -catenin信号传导途径（可能被抗氧化剂或铁螯合剂逆转）而影响高危MDS患者的基因稳定性，并损害MSC 。