American Association for Cancer Research
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Supplementary Table S11 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia

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posted on 2023-07-07, 08:20 authored by 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, Gael Roué, Nawad Hakim, Anne S. Dejean, Petros Tsantoulis, Clément Larrue, Didier Bouscary, Jerome Tamburini, Jean-Emmanuel Sarry

Table S11


Ligue Nationale de Lutte contre le Cancer

Cancer Research UK (CRUK)

Institut National Du Cancer (INCa)



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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