C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3 -Mutant Leukemia

• Published in: Cancer discovery 2023-07, Vol.13 (7), p.1720-1747
• Main Authors: 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, 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, Loo, Sun, Wei, Andrew, 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, Guillou, Hervé, Roué, Gael, Hakim, Nawad, Dejean, Anne, Tsantoulis, Petros, Larrue, Clément, Bouscary, Didier, Tamburini, Jerome, Sarry, Jean-Emmanuel
• Format: Article
• Language: English
• Subjects: Analytical chemistry; Biochemistry; Biochemistry, Molecular Biology; Cancer; Chemical Sciences; Life Sciences
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-22-0411

Abstract 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. Significance: 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