Numb调控Notch信号通路在急性髓细胞性白血病发病中的功能研究

The inhibitory role of Numb in Notch signaling pathway is involved in determining certain cancer or neural stem cells differentiation, proliferation and apoptosis. Studies showed that loss/low Numb expression, low Notch receptor-activity and decreases of Notch target genes’ expression were found in AML patients. However, our previous study demonstrated that Numb expression was significantly up-regulated in AML patients, which was correlated with the expression of several Notch receptors. Therefore, the expression of Notch receptors, ligands and target genes’ expression in AML patients, and Notch receptor transcriptional activities can be further investigated. In addition, it is necessary to reveal the mechanism of Numb in regulating Notch signaling pathway and its role in leukemic cell malignant clonal proliferation. Thus, this study is aimed to detect the mRNA and protein expression levels of Numb, Notch receptors/ligands, Hes1, Hey1 and NICD, and to analyze the mechanism of Numb in regulating Notch signaling pathway in AML patients. Furthermore, we will explore how the regulation of Notch signaling pathway by Numb affects leukemic cells by comparing and analyzing the changes of Notch signaling pathway, cell aggressiveness, apoptosis, proliferation and cell-cycle profile in AML cells after Numb gene knock-out or knock-in. These results may provide novel strategies and theoretical basis for the treatment and prevention of AML.

Numb抑制Notch信号通路，可以决定某些肿瘤或神经干细胞命运。已有研究发现AML中Numb表达缺失/低下，Notch受体活性降低且靶基因表达下降，但我们的前期检测结果显示AML患者Numb过表达，且与Notch受体表达相关。因此，AML中Notch信号受/配体和靶基因表达、受体转录活性以及Numb调控Notch信号通路在白血病细胞恶性克隆增生中的作用机制尚需深入探索。本课题拟通过检测AML患者（初诊、缓解）和对照的Numb、Notch受/配体、Hes1、Hey1及NICD的表达及Notch信号通路转录活性，揭示AML中Numb蛋白水平与Notch信号通路的关系；通过Numb基因敲除/敲入进一步确认其对Notch信号通路的影响，并检测AML细胞侵袭力、凋亡、增殖与周期等的变化，明确Numb调控Notch信号通路在AML发病中的功能。期望为AML防治提供新思路和必要的理论依据。