GATA-1/miR-150/MYB通路调控低危MDS巨核细胞分化的机制及干预研究

低危MDS主要临床特征是难治性血细胞减少，需要长期昂贵的支持治疗，给患者和社会带来沉重负担，其治疗成为研究热点。课题组利用生物信息学手段筛选出治疗低危MDS的药物依硫磷酸（AMF），临床研究发现AMF能改善低危MDS巨核细胞分化障碍，提高血小板数量，但机理不明。我们前期研究发现AMF能诱导巨核细胞系Dami分化，此过程伴随转录因子GATA-1入核增加及miR-150表达升高，生物信息学分析提示AMF治疗低危MDS可能和GATA-1/miR-150/MYB通路有关。本研究拟用细胞系验证AMF通过GATA-1/miR-150/MYB通路促进巨核细胞分化，用脐血和骨髓原代细胞验证此通路和低危MDS巨核细胞分化障碍的关系，最终将低危MDS骨髓GATA-1、miR-150、MYB的表达水平结合临床数据综合分析，找出预测AMF治疗低危MDS疗效的分子标记，为临床MDS的分层治疗提供理论基础。

The main clinical feature of low-risk MDS is refractory cytopenia. It needs long term and expensive supportive care, which brings heavy burdens to patients and society. Therefore, its treatment has become a research hotspot. We screen out amifostine (AMF) as a potential drug treating low-risk MDS by bioinformatics. Clinical study found that AMF could improve dysmegakaryocytopoiesis and increase the number of blood cells of low-risk MDS, but the mechanism is still not clear. Our previous study found that AMF could induce Dami cell differentiation, which is accompanied with an increased nuclear translocation of GATA-1 and miR-150 expression. Bioinformatics found that amifostine may promote megakaryocyte differentiation in low-risk MDS by GATA-1/miR-150/MYB pathway. In this study, we will figure out the role of this pathway on amifostine's promoting differentiation of Dami cells, and verify the relationship between GATA-1/miR-150/MYB pathway and dysmegakaryocytopoiesis of low-risk MDS on human primary cells. Finally, we will comprehensively analyze the relationship between clinical data and expression of GATA-1, miR-150, and MYB of low-risk MDS bone marrow cells. And we will find out a molecular marker to predict the efficacy of AMF in low-risk MDS, which could provide a theoretical basis for clinical stratified treatment of MDS.