C/EBPa 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 2023-04-03,Volume 13,Issue #7,Page 1720-1747
Journal Title: Cancer DIscovery
Abstract: While transcription factor C/AAT-enhancer binding protein a (C/EBPa) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPa 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/EBPa regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPa inactivation decreased mono-unsaturated 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/EBPa function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
Publisher: AACR
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
Research Division(s): Blood Cells And Blood Cancer
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: 2023-04-18 01:58:58

Last Modified: 2023-07-12 08:28:29