C/EBPa使FLT3突变白血病依赖于脂肪酸合成途径，并容易受到脂质氧化应激引起的铁死亡的影响。
C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia.
发表日期：2023 Apr 03
作者：
Marie Sabatier, Rudy Birsen, Laura Lauture, Sarah Mouche, Paolo Angelino, Jonas Dehairs, Lea Goupille, Ismael Boussaid, Mael Heiblig, Emeline Boet, Ambrine Sahal, Estelle Saland, Juliana C Santos, Marc Armengol, Miranda Fernandez-Serrano, Thomas Farge, Guillaume Cognet, Federico Simonetta, Corentin Pignon, Antoine Graffeuil, Celine Mazzotti, Herve Avet-Loiseau, Oceane Delos, Justine Bertrand-Michel, Amelie Chedru, Vilma Dembitz, Paolo Gallipoli, Natasha S Anstee, Sun Loo, Andrew H Wei, Martin Carroll, Armelle Goubard, Remy Castellano, Yves Collette, Francois Vergez, Veronique Mansat-De Mas, Sarah Bertoli, Suzanne Tavitian, Muriel Picard, Christian Recher, Nathalie Bourges-Abella, Fanny Granat, Olivier Kosmider, Pierre Sujobert, Benoit Colsch, Carine Joffre, Lucille Stuani, Johannes V Swinnen, Herve Guillou, Gael Roue, Nawad Hakim, Anne S Dejean, Petros Tsantoulis, Clement Larrue, Didier Bouscary, Jerome Tamburini, Jean-Emmanuel Sarry
来源：
Cell Death & Disease
摘要：
转录因子C/AAT-增强子结合蛋白a（C/EBPa）在正常和白血病分化中至关重要，但其对癌症细胞和代谢稳态的作用尚不清楚。在这里，多组学分析揭示了C/EBPa和类酪氨酸激酶3（FLT3）的协同激活，增强了在体内和FLT3突变急性髓系白血病（AML）患者中的脂质合成。在机制上，C/EBPa调节FASN-SCD轴以促进脂肪酸（FA）生物合成和脱饱和。我们进一步证明，FLT3或C/EBPa失活通过下调SCD减少了单不饱和FA在膜磷脂中的融合。因此，SCD抑制增加了对脂质氧化应激的敏感性，该应激被结合FLT3和谷胱甘肽过氧化物酶4抑制来触发脂质氧化应激，增强FLT3突变AML细胞的铁死亡。总之，我们的研究揭示了C/EBPa在脂质稳态和适应氧化应激中的功能，以及FLT3突变AML对铁死亡的先前未报道的易感性，具有前景的治疗应用。
While transcription factor C/AAT-enhancer binding protein a (C/EBPa) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPa and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPa regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPa inactivation decreased mono-unsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPa function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.