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

Sabatier, M; Birsen, R; Lauture, L; Mouche, S; Angelino, P; Dehairs, J; Goupille, L; Boussaid, I; Heiblig, M; Boet, E; Sahal, A; Saland, E; Santos, JC; Armengol, M; Fernandez-Serrano, M; Farge, T; Cognet, G; Simonetta, F; Pignon, C; Graffeuil, A; Mazzotti, C; Avet-Loiseau, H; Delos, O; Bertrand-Michel, J; Chedru, A; Dembitz, V; Gallipoli, P; Anstee, NS; Loo, S; Wei, AH; Carroll, M; Goubard, A; Castellano, R; Collette, Y; Vergez, F; Mansat-De Mas, V; Bertoli, S; Tavitian, S; Picard, M; Recher, C; Bourges-Abella, N; Granat, F; Kosmider, O; Sujobert, P; Colsch, B; Joffre, C; Stuani, L; Swinnen, JV; Guillou, H; Roue, G; Hakim, N; Dejean, AS; Tsantoulis, P; Larrue, C; Bouscary, D; Tamburini, J; Sarry, JE

Author(s): Sabatier, M; Birsen, R; Lauture, L; Mouche, S; Angelino, P; Dehairs, J; Goupille, L; Boussaid, I; Heiblig, M; Boet, E; Sahal, A; Saland, E; Santos, JC; Armengol, M; Fernandez-Serrano, M; Farge, T; Cognet, G; Simonetta, F; Pignon, C; Graffeuil, A; Mazzotti, C; Avet-Loiseau, H; Delos, O; Bertrand-Michel, J; Chedru, A; Dembitz, V; Gallipoli, P; Anstee, NS; Loo, S; Wei, AH; Carroll, M; Goubard, A; Castellano, R; Collette, Y; Vergez, F; Mansat-De Mas, V; Bertoli, S; Tavitian, S; Picard, M; Recher, C; Bourges-Abella, N; Granat, F; Kosmider, O; Sujobert, P; Colsch, B; Joffre, C; Stuani, L; Swinnen, JV; Guillou, H; Roue, G; Hakim, N; Dejean, AS; Tsantoulis, P; Larrue, C; Bouscary, D; Tamburini, J; Sarry, JE;
Details: Publication Year 2023-07-07,Volume 13,Issue #7,Page 1720-1747
Journal Title: Cancer Discovery
Publication Type: Research article
Abstract: Although transcription factor CCAAT-enhancer binding protein alpha (C/EBPalpha) 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/EBPalpha 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/EBPalpha 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/EBPalpha 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/EBPalpha 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/EBPalpha 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.
Publisher: American Association for Cancer Research
Keywords: Humans; CCAAT-Enhancer-Binding Protein-alpha/genetics/metabolism; fms-Like Tyrosine Kinase 3/genetics/metabolism; *Ferroptosis; Fatty Acids; *Leukemia, Myeloid, Acute/drug therapy/genetics/metabolism; Mutation; Oxidative Stress; Protein Kinase Inhibitors/therapeutic use; Cell Line, Tumor
Department(s): Clinical Haematology
PubMed ID: 37012202
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-22-0411
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-24 04:47:22

Last Modified: 2024-07-16 04:38:32