Yin Feng, Yang Jing, Luo Hao, Yu Tiantian, Lu Wenhua, Zhao Mingyue, Du Hongli, Wen Shijun, Huang Peng, Hu Yumin
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Cancer Metabolism and Intervention Research Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
Metabolomics Research Center, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, 510080, China.
Cell Death Dis. 2025 Apr 22;16(1):327. doi: 10.1038/s41419-025-07661-6.
FMS-like tyrosine kinase 3-internal tandem duplication (FLT3/ITD) is a common driver mutation that presents with a high leukemic burden and its impact on metabolic homeostasis remains to be further investigated. Here, we revealed that the oncogenic activation of FLT3/ITD induced upregulation of target genes of sterol regulatory element-binding proteins (SREBPs) in vivo and in acute myeloid leukemia patients. Quizartinib is a second-generation FLT3 inhibitor that selectively inhibits the activating FLT3 mutations. We demonstrated the critical role of SREBP1 degradation in conferring the response of FLT3/ITD cells to quizartinib. Mechanistically, quizartinib facilitated degradation of the precursor form of SREBP1 via the FLT3/AKT/GSK3 axis and reduced protein levels of its target gene fatty acid synthase (FASN). Lipidomics analysis by Liquid Chromatography Mass Spectrometry (LC-MS) demonstrated that inhibition of FLT3 altered global levels of phospholipids including reduction of cardiolipin, leading to subsequent loss of mitochondrial membrane potential. Pharmacological inhibition of SREBP1 or FASN sensitized FLT3/ITD leukemia cells to quizartinib. Quizartinib combined with SREBP inhibitor fatostatin or FASN inhibitor orlistat provided substantial therapeutic benefit over monotherapies in the murine FLT3/ITD leukemia model. Our results indicated the mechanistic link between FLT3/ITD and SREBP degradation and suggested the combination therapy via targeting FLT3/SREBP/FASN axis.
FMS样酪氨酸激酶3内部串联重复（FLT3/ITD）是一种常见的驱动突变，与高白血病负荷相关，其对代谢稳态的影响仍有待进一步研究。在此，我们揭示了FLT3/ITD的致癌激活在体内和急性髓系白血病患者中诱导了固醇调节元件结合蛋白（SREBPs）靶基因的上调。奎扎替尼是一种第二代FLT3抑制剂，可选择性抑制激活型FLT3突变。我们证明了SREBP1降解在赋予FLT3/ITD细胞对奎扎替尼反应中的关键作用。机制上，奎扎替尼通过FLT3/AKT/GSK3轴促进SREBP1前体形式的降解，并降低其靶基因脂肪酸合酶（FASN）的蛋白水平。通过液相色谱质谱联用（LC-MS）进行的脂质组学分析表明，抑制FLT3会改变包括心磷脂减少在内的磷脂整体水平，导致随后线粒体膜电位的丧失。对SREBP1或FASN的药理抑制使FLT3/ITD白血病细胞对奎扎替尼敏感。在小鼠FLT3/ITD白血病模型中，奎扎替尼与SREBP抑制剂法托司他汀或FASN抑制剂奥利司他联合使用比单一疗法提供了更大的治疗益处。我们的结果表明了FLT3/ITD与SREBP降解之间的机制联系，并提出了通过靶向FLT3/SREBP/FASN轴的联合治疗方法。
