Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer discovery, 2023-07, Vol.13 (7), p.1720-1747

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.