miR-138和miR-129-5p在骨髓增生异常综合征发生发展中的作用及其机制研究

Myelodysplastic syndrome (MDS) are a group of heterogeneous myeloid neoplasms that derived from hematopoietic stem cells. Due to its unclear molecular mechanism, the diagnosis and prognosis prediction of MDS is still difficult. In our preliminary work, we found that stem cell factor SALL4 and target genes were positively correlated with high risk and malignant degree of MDS subtypes. But there was no report on whether miRNAs were involved in the regulation of this pathway. Compared with MDS patients with low degree, those with high degree had a significantly higher expression level of miR-138 and miR-129-5p. We predicted that miR-138 and miR-129-5P would conservatively target on BMI1 and SALL4 and, simultaneously, on three activator genes..In this study, we investigate, for the first time, the relationship between miR-138/129-5p and subtypes, classification of risks and prognosis of MDS. We will also study the effect of two miRNAs on hematopoietic stem/progenitor cell cycle, proliferation, differentiation and clone formation. In vitro experiments were conducted to identify the target of miR-138/129-5p and the relationship between the miRNAs, SALL4, Wnt/β-catenin and BCL2 pathway. In conclusion, this study focuses on whether miR-138/129-5p is qualified as a new marker for MDS diagnose and diagnosis prediction for therapy.

骨髓增生异常综合征（MDS）是复杂的造血干细胞异质性疾病，由于发病机制尚不清楚，该疾病诊断困难、进展预后很难预测。我们近期发现干细胞因子SALL4通路与MDS恶性程度和高风险呈正相关，但miRNA是否参与其调控尚无报道。抑癌因子miR-138和miR-129-5p在高风险组显著下调，预测发现分别保守作用于BMI1、SALL并同时潜在作用于多个活化因子。本课题首次探讨miR-138/129-5p与MDS分型、危险分级等指标的关系,研究其对造血干祖细胞增殖分化、凋亡及集落形成等特性的影响，明确miR-138/129-5p的靶基因并检测其对SALL4、Wnt/β-catenin和BCL2通路的调控作用，探讨miR-138/129-5p能否成为MDS分型、判断进展的新指标，为分子靶向治疗提供新的契机。