Asb2在急性T淋巴细胞白血病中的作用及干预

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive .hematologic malignancy characterized by abnormal proliferation of immature T cells. Although the chemotherapy is able to relieve symptoms, it might cause serious adverse effects on multiple organs. In addition, the T-ALL patients who were treated by the chemotherapy are also at high risk of overt metastatic relapse. Therefore, the targeted therapy for leukemia cells has been considered as a promising therapy. Previous findings demonstrated that Notch-induced activation of NF-кB plays pivotal roles in the onset and development of T-ALL. However, the underlying mechanism remains unclear. Our previous findings suggested that Notch might induce the activation of NF-кB by stimulating the transcription of Asb2, which is an important constitutive component of E3 ligase complex. This project aims to investigate the role of Asb2 in mediating Notch-induced NF-кB activation in T-ALL cells, and verify if the specific suppression of expression or function of Asb2 can inhibit the proliferation of T-ALL cells and induce the apoptosis of T-ALL cells. This project will confirm the link between Notch and NF-кB signaling pathway, clarify the mechanism by which Notch signal up-regulates NF-кB activity and test the feasibility of treatment of T-ALL by targeting Asb2, thus providing valuable theoretical and experimental basis for new targeted therapy for T-ALL.

急性T 淋巴细胞白血病 (T-ALL) 由T淋巴细胞异常增殖所致。化疗虽可有效缓解病情，但副作用大，且易广泛转移和复发。白血病细胞的靶向治疗已成为白血病治疗的发展趋势。前期研究发现Notch信号上调NF-кB活性是导致T淋巴细胞异常增殖的主要原因，其具体调控机制不明。我们研究提示Notch信号很可能是通过上调泛素连接酶E3复合体的主要构成蛋白Asb2的转录而激活NF-кB。本项目将研究Notch信号上调NF-кB活性的具体机制，探讨和验证Asb2蛋白在二者中的关键作用，并抑制Asb2蛋白的表达和功能以期达到抑制T-ALL细胞的异常增殖、促进凋亡、治疗T-ALL的目的。本项目将从理论上进一步确定T-ALL细胞中Notch信号与NF-кB信号的纵向联系，阐明Notch信号对NF-кB信号的调控机制，验证以Asb2为靶向基因治疗的靶点的有效性和可行性，为临床更为有效地治疗提供理论和实验依据。

Asb2α是一个E3泛素连接酶的底物识别亚基，其在骨髓造血细胞的分化中起到重要作用。众所周知，在急性T淋巴细胞白血病（T-ALL）中，致癌基因Notch1可以活化NF-κB信号通路。另外，在其它细胞中，Notch1被发现可以上调Asb2α的转录。我们的研究结果发现在T-ALL细胞中，Notch1可以活化Asb2α的转录，紧接着被表达的Asb2α蛋白又促使了 NF-κB 的活化。我们的研究进一步发现Asb2α是通过诱导IκBα的泛素化和降解，从而释放和活化 NF-κB 。更为重要的是 Asb2α 的表达抑制可以促进T-ALL细胞的凋亡并抑制T-ALL细胞的增殖。以上所有的研究结果显示Asb2α 作为新的药物靶点治疗T-ALL具有有效性和可行性。