BCL-2抑制剂Venetoclax协同高三尖杉酯碱治疗早期前体T细胞急性淋巴细胞白血病及其分子机制研究

早期前体T细胞急性淋巴细胞白血病（ETP-ALL）是一类病程进展快、患者预后差的T-ALL亚型，临床上目前没有针对性治疗方法。基于文献调研和临床实践，我们创新性地提出了BCL-2抑制剂Venetoclax与高三尖杉酯碱（HHT）的联合用药方案，并在体内外实验及临床实践中均观察到二者对ETP-ALL的协同作用，拟对二者的协同机制进行深入探究。我们推测Venetoclax与HHT通过分别抑制BCL-2和MCL-1蛋白，诱导线粒体凋亡途径，达到协同治疗ETP-ALL的作用。此外，我们计划采用RNA-seq筛选并探究其他在该方案中发挥关键作用的信号通路。本课题拟验证Venetoclax与HHT联合给药方案的安全性与有效性；阐明该方案对ETP-ALL产生治疗作用的机制；寻找与该方案配伍的常规化疗药物，并推广以Venetoclax与HHT为基础的联合方案作为其他耐药难治血液肿瘤的潜在治疗策略。

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinctive subtype of T cell acute lymphoblastic leukemia (T-ALL), which is extremely aggressive and associated with a worse prognosis. Currently，there is no effective targeted therapy for this subtype. Based on literature and clinical practice, we have innovatively proposed a combined therapy of BCL-2 inhibitor Venetoclax and homoharringtonine (HHT) on the treatment of ETP-ALL, and observed a significantly synergistic effect in vitro, in vivo and in clinical practice. We put forward a scientific hypothesis: Venetoclax and HHT could achieve synergistic effects by inhibiting BCL-2 and MCL-1 proteins respectively. In addition, RNA-seq experiments are also required to discover other key cellular pathways involved in the combined therapy. This project intends to verify the safety and effectiveness of the combination treatment; clarify the synergistic mechanism of the two agents on ETP-ALL, and provide a combined regimen based on Venetoclax and HHT as a potential treatment strategy for ETP-ALL and other resistant and refractory hematological malignancies.