FLT3-ITD突变通过激活PI3K-Akt信号通路上调SREBP1表达促进细胞脂肪代谢改变

Flt-3 internal tandem duplication (FLT3-ITD) in transmembrane region is the most frequently happened mutation in FLT3 gene and always associated with poor prognosis. FLT3 inhibitors have shown promising efficacies in AML，however, the duration of clinical response is short because of the rapid development of resistance, finding new strategy to improve the drug efficacies is of crucial importance. In our preliminary experiments, we found genes correlated with lipid synthesis were significantly up-regulated in BaF3-ITD cells comparing with BaF3 cells, which means the FLT3-ITD mutant cells may have more active lipogenesis, and this phenomenon is probably correlated with PI3K-Akt activation and SREBP1 up-regulation. Based on this, we speculate that FLT3-ITD mutation up-regulated the expression of SREBP1 by activating the PI3K-Akt signaling pathway and promoted the fatty acid metabolism. In order to confirm my speculation, we would further conduct the following experiments: Firstly, by using mass spectrometric detection method to compare the fatty acid metabolic differences between BaF3/ITD and BaF3 cells. Secondly, illustrating the underlying mechanism of this phenomenon by studying the relationship between PI3K-Akt and SREBP1. Thirdly, Compare the drug sensitivity of SREBP1 inhibitors in the FLT3-ITD mutant and wild type cells in vivo. Fourthly, confirm the drug efficacy of SREBP1 inhibitors in the animal experiment and provide new strategy for the treatment of FLT3-ITD mutant AML. This project is expected to provide new ideas for the treatment of FLT3-ITD mutant leukemia.

FLT3-ITD是最常见的FLT3基因突变类型，与AML的不良预后相关，也是治疗难点。FLT3抑制剂是目前的研究热点但耐药问题不容忽视，如何提高其药物治疗效果至关重要。本课题预实验发现FLT3-ITD突变细胞株相较于野生型细胞的脂肪代谢相关基因表达升高，且该现象与PI3K-Akt通路的激活并上调SREBP1相关。因此推测：FLT3-ITD通过激活PI3K-Akt通路上调SREBP1表达促进细胞脂肪代谢改变。本课题拟：1.进一步通过质谱检测验证两种细胞的脂肪代谢差异。2.通过基因沉默、基因高表达及免疫荧光等实验手段研究FLT3-ITD突变与PI3K-Akt及SREBP1之间的相互作用关系，并探讨其机制；3.体内体外实验明确脂肪代谢抑制剂对FLT3-ITD突变白血病的药物治疗作用，提高FLT3-ITD突变型AML的药物治疗效果。本项目有望为FLT3-ITD突变型白血病的治疗提供新思路。

FLT3-ITD是AML最常见的基因突变类型，与不良预后相关，也是治疗难点。FLT3抑制剂是目前的研究热点但耐药问题不容忽视，如何提高其药物治疗效果至关重要。本项目通过代谢组学技术手段，鉴定出BaF3-ITD细胞株和亲代BaF3细胞株之间的代谢差异，提出FLT3-ITD突变可诱导细胞发生显著的代谢改变，主要发生改变的代谢物成分集中在脂质相关物质中，占比约30%。这一改变相关的驱动信号通路为PI3K-AKT-SREBP通路，使用SREBP1抑制剂Fatostatin联合PI3K-AKT通路的抑制剂(MK2206、U0126、索拉非尼)可以达到有效杀伤FLT3-ITD突变的白血病细胞，而该治疗方案对于FLT3野生型细胞株无该作用。本项目有望为发生FLT3-ITD突变的白血病类型患者提供新的治疗方案，具有光明的应用前景。

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