Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.

中文翻译：

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年龄相关的炎症性骨髓微环境诱导无效的促红细胞生成，类似于del（5q）MDS。

贫血是骨髓增生异常综合症（MDS）的特征。MDS贫血的机制尚不清楚。使用小鼠遗传学方法，在这里我们显示mDia1和miR-146a的双重缺陷，编码在5q染色体上，通常在MDS中缺失（del（5q）MDS），引起年龄相关性贫血和模仿人类MDS的无效红细胞生成。我们证明了老化的骨髓微环境对于这些小鼠无效的红细胞生成的发展很重要。损伤相关分子模式分子（DAMPs）的水平在衰老的骨髓中增加，在mDia1 / miR-146a双敲除小鼠的骨髓源性抑制细胞（MDSCs）中诱导TNFα和IL-6上调。机械上，我们发现，TNFα和IL-6的病理水平抑制了红系集落的形成，并通过活性氧诱导的caspase-3激活和凋亡而差异性地影响了终末红细胞生成。用全反式视黄酸处理mDia1 / miR-146a双敲除小鼠，可促进MDSC的分化并改善炎症性骨髓微环境，可显着挽救贫血和无效的红细胞生成。我们的研究强调了del（5q）MDS中无效的红细胞生成的发病机理中，微环境老化和遗传异常的双重作用。促进MDSCs的分化并改善炎症性骨髓微环境，显着挽救贫血和无效的红细胞生成。我们的研究强调了del（5q）MDS中无效的红细胞生成的发病机理中，微环境老化和遗传异常的双重作用。促进MDSCs的分化并改善炎症性骨髓微环境，显着挽救贫血和无效的红细胞生成。我们的研究强调了del（5q）MDS中无效的红细胞生成的发病机理中，微环境老化和遗传异常的双重作用。