TAL1复合体上调S1PR3激活NOTCH1信号促进T-ALL发生发展的机制研究

急性T淋巴细胞白血病(T-ALL)是儿童难治与易复发白血病。转录因子TAL1异常与NOTCH1信号协同是T-ALL发生发展的关键，其协同机制研究有望阐明T-ALL机制并找到药物靶点。延续以往，课题组近期发现TAL1+亚群T-ALL患者肿瘤细胞中磷酸鞘氨醇受体3(S1PR3)表达增高；TAL1联合LMO2可促进T-ALL细胞S1PR3表达与NOTCH1下游基因改变；抑制S1PR3可延缓鼠移植瘤进展。基于此，本项目提出科学假设“TAL1联合LMO2复合体，通过TAL1转录调控复合体中的MYB，与S1PR3转录调控区特异结合，上调S1PR3转录与表达，激活NOTCH1信号，促进T-ALL发生发展”，拟利用T-ALL体内外模型、条件敲除鼠、RNA-Seq等策略，深入探讨TAL1复合体促进T-ALL发生发展的分子机制，为阐释难治性白血病发病机理与寻找新型靶向药物奠定基础，具有重要理论意义和应用前景。

Acute T cell lymphoblastic leukemia (T-ALL) is a refractory and relapsed leukemia in children. The cooperation of abnormal transcription factor TAL1 expression and activation NOTCH1 signal are the keys to the tumorigenesis and development of T-ALL, which is a promising way to find new therapeutic targets and medicine, by illustrating the molecular mechanism for their synergistion. Our research team continued the previous research and recently found that the expression of sphingosine-1-phosphate receptor 3 (S1PR3) was enhanced in the TAL1+ T-ALL subgroup cells. Combined inducing TAL1 with LMO2 in T-ALL cells could promote the expression of S1PR3 and the alteration expression of NOTCH1 downstream genes. Knocking down the expression of S1PR3 could inhibit the progression of T-ALL mice xenograft. Based on these findings, we firstly propose the hypothesis of “The complex of TAL1 binding with LMO2 promotes the occurrence and development of T-ALL, which is through transcription factor MYB, one of the TAL1/GATA3/RUNX1/MYB key transcript regulation circuit complex, specifically binding to the cis-regulatory modules of S1PR3, to up-regulate S1PR3 transcript and expression, to activate NOTCH1 signal and its downstream pathway”, and then intend to use T-ALL model in vitro and in vivo, by applying the research strategies of S1PR3 conditional knockout mice, RNA-Seq and other cutting-edge technical strategies, to further explore the molecular mechanisms of TAL1 complex promoting the pathogenesis and development of T-ALL. This project will lay a solid foundation for explaining the pathogenesis of refractory leukemia, and find new targeted therapeutic drugs for T-ALL, which has important theoretical significance and clinical application prospects.