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Sabatier, Marie; Birsen, Rudy; Lauture, Laura; Mouche, Sarah; Angelino, Paolo; Dehairs, Jonas; Goupille, Léa; Boussaid, Ismael; Heiblig, Maël; Boet, Emeline; Sahal, Ambrine; Saland, Estelle; Santos, Juliana C; Armengol, Marc; Fernández-Serrano, Miranda; Farge, Thomas; Cognet, Guillaume; Simonetta, Federico; Pignon, Corentin; Graffeuil, Antoine; Mazzotti, Céline; Avet-Loiseau, Hervé; Delos, Océane; Bertrand-Michel, Justine; Chedru, Amélie; Dembitz, Vilma; Gallipoli, Paolo; Anstee, Natasha S; Loo, Sun; Wei, Andrew H; Carroll, Martin; Goubard, Armelle; Castellano, Rémy; Collette, Yves; Vergez, François; Mansat-De Mas, Véronique; Bertoli, Sarah; Tavitian, Suzanne; Picard, Muriel; Récher, Christian; Bourges-Abella, Nathalie; Granat, Fanny; Kosmider, Olivier; Sujobert, Pierre; Colsch, Benoit; Joffre, Carine; Stuani, Lucille; Swinnen, Johannes V; Guillou, Hervé; Roué, Gael; Hakim, Nawad; Dejean, Anne S; Tsantoulis, Petros; Larrue, Clément; Bouscary, Didier; Tamburini, Jerome; Sarry, Jean-Emmanuel
Cancer discovery, 07/2023, Volume: 13, Issue: 7Journal Article
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 in vivo and in patients with FLT3-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 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/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. FLT3 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. This article is highlighted in the In This Issue feature, p. 1501.
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