来那度胺抑制CD33-ITIM信号调节MDSC免疫抑制活性和治疗MDS的分子机制研究

Myelodysplastic syndrome (MDS) is a hematopoietic stem cell malignanttumor，an acquired disease associated with suppressive cytokines and mediators present in the bone marrow microenvironment. The over-expressed CD33 and its signaling may play an important role in MDSC differentiation and worth discussing. Lenalidomide (LEN) is the only FDA approved for MDS targeting drug, but the specific mechanism is unknown. Firstly, we verified the effect of CD33 in regulation of MDSC. The results showed that overexpression of CD33 blocked the maturation of MDSC, reduced the BFU-E colony formation. Secondly, the results shows that LEN can inhibit the activity of SHP1/SHP2 in vitro. Therefore, we hypothesized that, CD33 signal pathway may be involved in regulating the activity of MDSC. LEN as a phosphatase inhibitor, may be conjunced to SHP1/SHP2 to regulate CD33 signaling pathway, thereby regulation of MDSC maturation and activity. To confirm this hypothesis, this research will take CD33 as the breakthrought point, elaborate the regulatory effect of LEN on MDSC and CD33-ITIM signal pathway and target CD33-ITIM signaling pathway to regulate the molecular mechanism of MDSC. The completion of this project will deepen our understanding of the biology of MDSC in MDS, and lay the foundation of CD33 and MDSC for the research of tumor treatment, provide a potential new therapeutic strategies for MDS molecular therapy.

骨髓增生异常综合征（MDS)是造血干细胞恶性肿瘤，骨髓微环境中存在大量髓源性抑制细胞（MDSC），其高表达CD33及其信号通路是否调控MDSC活性值得探讨。来那度胺（LEN）是唯一获得FDA批准用于MDS治疗的靶向药物，但具体机制并不详。我们预实验确证了CD33在MDSC调节中的作用，结果显示CD33过表达阻断MDSC成熟，减少BFU-E集落形成；其次，验证了LEN能够体外抑制SHP1/SHP2活性。因此我们推测，CD33信号通路可能参与调控MDSC的活性，LEN作为磷酸酶抑制剂，可能靶向CD33通路中SHP1/SHP2位点，抑制MDSC的CD33-ITIM信号通路。因此，本课题将阐述CD33-ITIM信号通路对MDSC的调控作用及LEN通过靶向CD33-ITIM信号通路调控MDSC的分子机制。本课题的完成，将深化对MDS中MDSC生物学行为的认识，为MDS靶向治疗提供新的潜在治疗策略。

骨髓增生异常综合征（MDS）是造血干细胞恶性肿瘤，骨髓微环境中存在大量髓源性抑制细胞（MDSC），其高表达CD33及其信号通路是否调控MDSC活性值得探讨。来那度胺（LEN）是唯一获得FDA批准用于MDS治疗的靶向药物，但具体机制并不详。本课题研究表明，MDS患者骨髓MDSC增多，其释放效应分子导致MDS骨髓微环境改变，抑制HSC/HPC发育；CD33-ITIM信号通路参与了MDSC成熟调控，抑制其成熟；LEN通过靶向CD33-ITIM信号通路SHP1/SHP2位点促进MDSC成熟，从而抑制其免疫抑制作用。本课题的完成，深化对MDS中MDSC生物学行为的认识，为MDS靶向治疗提供新的潜在治疗策略。