Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Cancer Biology PhD Program, H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida, Tampa, FL, USA.
Leukemia. 2018 Apr;32(4):1023-1033. doi: 10.1038/leu.2017.326. Epub 2017 Nov 16.
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.
骨髓增生异常综合征（MDS）的特征是贫血。MDS 贫血的机制尚不清楚。我们采用小鼠遗传方法，在此表明，位于 5q 染色体上且在 MDS 中常见缺失的 mDia1 和 miR-146a 的双重缺失（del(5q) MDS）会导致与人类 MDS 相似的年龄相关性贫血和无效造血。我们证明，老化的骨髓微环境对于这些小鼠无效造血的发展很重要。在 mDia1/miR-146a 双敲除小鼠中，衰老骨髓中增加的损伤相关分子模式分子（DAMPs）诱导髓系来源的抑制细胞（MDSC）中 TNFα 和 IL-6 的上调。在机制上，我们揭示病理性 TNFα 和 IL-6 水平通过活性氧诱导的半胱天冬酶-3 激活和凋亡抑制红系集落形成并通过影响终末红细胞生成而产生差异影响。用全反式视黄酸治疗 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，显著改善贫血和无效造血。我们的研究强调了衰老微环境和遗传异常在 del(5q) MDS 无效造血发病机制中的双重作用。
