GLI1和PI3K/AKT在急性髓系白血病细胞中相互作用及具体机制的研究

Refractory and relapse are the main obstacles in the therapy of acute leukemia, the most common type of hematological malignant tumor. Based on the support of our last NSFC grant, we found that side population(SP) in acute myeloid leukemia(AML) and expression of ABCG2 were regulated by PI3K/AKT signaling pathway, which affected the fate of AML. Recent studies suggested that, inhibition of GLI1 could enhance AML drug sensitivity through PI3K/AKT pathway. However, the cross-talk between GLI1 and PI3K/AKT pathway remains unclear. In this project, CRISPR-based knockout, CHIP-chip, RNA-seq were utilized to explore how GLI1 affecting the drug-resistant in AML through PI3K/AKT pathway. Then AML cells will be screened out for potential targeted drugs by High Throughput Drug Screening Platform. All experiments might be performed in AML cell lines, clinic sample and animal models. The proposed studies will provide new strategies in AML targeting therapy, which might improve the outcomes of patients.

急性白血病（AL）作为血液系统高发恶性肿瘤，其耐药与复发一直是该领域关注焦点之一。我们的前期研究发现PI3K/AKT信号通路调控急性髓系白血病（AML）细胞干细胞旁系群体（SP）及耐药基因ABCG2的表达，从而影响白血病的化疗疗效和转归，最近研究发现信号分子GLI1可通过PI3K/AKT信号通路调控AML对药物的敏感性。然而，他们之间的相互作用及具体机制仍不清楚。本课题拟利用CRISPR、CHIP-chip、RNA-seq和高通量药物/小分子化合物筛选等技术，在肿瘤细胞和动物模型中研究GLI1和PI3K/AKT的相互作用及具体机制，并筛选潜在的靶向药物/小分子化合物，为AML靶向治疗提供新思路。

急性白血病（AL）作为血液系统高发恶性肿瘤，其耐药与复发一直是该领域关注焦点之一。我们的前期研究发现信号分子GLI1可通过PI3K/AKT信号通路调控AML对药物的耐药性。然而，他们之间的相互作用及具体机制仍不清楚。本课题我们通过构建过表达和敲减GLI1急性髓系白血病稳转细胞系和小鼠成瘤实验来探索GLI1与PI3K/AKT信号通路互作影响AML耐药的具体作用机制。研究发现在AML中，GLI1通过与PIK3R1结合激活PI3K/AKT 通路活性，进而上调下游效应分子周期蛋白激酶（Cyclin D、CDK4/6）表达，最终促进AML细胞增殖、诱导AML细胞耐药。基于以上机制研究结果，我们进一步研究发现GLI1抑制剂GANT61联合CDK4/6抑制剂PD 0332991对可明显增强AML细胞对Ara-c敏感性。本项目的结果完善了GLI1与PI3K/AKT互作介导AML耐药机制研究，为复发/难治性AML患者靶向治疗提供了新的视角。