作者
Marie Sabatier,Rudy Birsen,Laura Lauture,Sarah Mouche,Paolo Angelino,Jonas Dehairs,Léa Goupille,Ismael Boussaid,Maël Heiblig,Emeline Boet,Ambrine Sahal,Estelle Saland,Juliana C. Santos,Marc Armengol,Miranda Fernández-Serrano,Thomas Farge,Guillaume Cognet,Federico Simonetta,Corentin Pignon,Antoine Graffeuil,Céline Mazzotti,Hervé Avet-Loiseau,Océane Delos,Justine Bertrand-Michel,Amélie Chedru,Vilma Dembitz,Paolo Gallipoli,Natasha S. Anstee,Sun Loo,Andrew H. Wei,Martin Carroll,Armelle Goubard,Rémy Castellano,Yves Collette,François Vergez,Véronique Mansat-De Mas,Sarah Bertoli,Suzanne Tavitian,Muriel Picard,Christian Récher,Nathalie Bourges-Abella,Fanny Granat,Olivier Kosmider,Pierre Sujobert,Benoit Colsch,Carine Joffre,Lucille Stuani,Johannes V. Swinnen,Hervé Guillou,Gaël Roué,Nawad Hakim,Anne S. Dejean,Petros Tsantoulis,Clément Larrue,Didier Bouscary,Jerome Tamburini,Jean-Emmanuel Sarry
摘要
<div>Abstract<p>Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism <i>in vivo</i> and in patients with <i>FLT3</i>-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through <i>SCD</i> 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 <i>FLT3</i>-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of <i>FLT3</i>-mutant AML to ferroptosis with promising therapeutic application.</p>Significance:<p><i>FLT3</i> mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML.</p></div>