靶向干扰素γ及其受体IFNGR1促进急性髓系白血病干细胞分化中的作用和机制

白血病干细胞（LSCs）是急性髓系白血病（AML）复发和难治的重要原因。我们前期从2千多种上市药物中筛选到CDK4/6抑制剂Abemaciclib可诱导LSCs分化，且与其他CDK4/6抑制剂相比，其对AML-LSCs诱导分化疗效更显著。通过靶标捕获分析发现，Abemaciclib可靶向干扰素γ（IFN-γ）。进一步研究提示Abemaciclib一方面通过靶向CDK4/6抑制细胞增殖；另一方面可通过抑制IFN-γ引起的促AML干性，从而诱导LSCs分化。本项目将从分子、细胞与整体水平：（1）证实Abemaciclib靶向IFN-γ促进LSCs分化的作用，探讨其作用的分子机制，为Abemaciclib用于复发型AML的治疗提供理论依据；（2）明确IFN-γ促AML干性的作用和新机制，探究IFN-γ及其受体IFNGR1的表达与AML患者预后的关系；为LSCs分化调控机制提供新观点。

Leukemia stem cell (LSCs) is an important cause of relapsed and refractory acute myeloid leukemia (AML). In the early stage, we screened a CDK4/6 inhibitor Abemaciclib from drug library (>2, 000 FDA approved drugs) , which can induce LSCs differentiation. Compared with other CDK4/6 inhibitors, Abemaciclib showed more significant activity in inducing AML-LSCs differentiation. Target capture analysis suggested that Abemaciclib could target to interferon-γ (IFN-γ). Further studies suggest that on the one hand, Abemaciclib inhibits cell proliferation by targeting CDK4/6; on the other hand, it can induce LSCs differentiation by inhibiting IFN- γ dependent AML stemness. This project will be performed in molecular, cellular and overall levels: (1) to confirm the role of Abemaciclib targeting IFN- γ in promoting LSCs differentiation, and to explore its molecular mechanism, so as to provide a new theoretical basis for the treatment of recurrent AML; (2) to clarify the role and new mechanism of IFN- γ in promoting the stemness of AML, to explore the relationship between the expression of IFN- γ and its receptor IFNGR1 and the prognosis of AML patients, and to provide a new point of view for the regulatory mechanism of LSCs differentiation.