C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia PMID: 37012202

ADC Targets in Oncology

2026-04-10

C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia

Cancer Discov. 2023 Apr 3;CD-22-0411. doi: 10.1158/2159-8290.CD-22-0411.

Marie Sabatier ¹ , Rudy Birsen ² , Laura Lauture ¹ , Sarah Mouche ³ , Paolo Angelino ⁴ , Jonas Dehairs ⁵ , Lea Goupille ¹ , Ismael Boussaid ² , Mael Heiblig ⁶ , Emeline Boet ¹ , Ambrine Sahal ¹ , Estelle Saland ⁷ , Juliana C Santos ⁸ , Marc Armengol ⁹ , Miranda Fernandez-Serrano ⁹ , Thomas Farge ¹⁰ , Guillaume Cognet ¹¹ , Federico Simonetta ³ , Corentin Pignon ¹ , Antoine Graffeuil ¹ , Celine Mazzotti ¹ , Herve Avet-Loiseau ¹² , Oceane Delos ¹ , Justine Bertrand-Michel ¹³ , Amelie Chedru ¹⁴ , Vilma Dembitz ¹⁵ , Paolo Gallipoli ¹⁵ , Natasha S Anstee ¹⁶ , Sun Loo ¹⁶ , Andrew H Wei ¹⁷ , Martin Carroll ¹⁸ , Armelle Goubard ¹⁹ , Remy Castellano ²⁰ , Yves Collette ²⁰ , Francois Vergez ²¹ , Veronique Mansat-De Mas ²¹ , Sarah Bertoli ²² , Suzanne Tavitian ²³ , Muriel Picard ²⁴ , Christian Recher ²⁵ , Nathalie Bourges-Abella ²⁶ , Fanny Granat ¹ , Olivier Kosmider ²⁷ , Pierre Sujobert ²⁸ , Benoit Colsch ¹⁴ , Carine Joffre ²⁹ , Lucille Stuani ¹ , Johannes V Swinnen ³⁰ , Herve Guillou ³¹ , Gael Roue ⁹ , Nawad Hakim ¹ , Anne S Dejean ³² , Petros Tsantoulis ³³ , Clement Larrue ⁷ , Didier Bouscary ² , Jerome Tamburini ² , Jean-Emmanuel Sarry ¹

Affiliations

1. Inserm and Universite de Toulouse, Toulouse, France.
2. Institut Cochin, Paris, France.
3. University of Geneva, Geneva, Switzerland.
4. SIB Swiss Institute of Bioinformatics, Lausanne, Vaud, Switzerland.
5. KU Leuven - University of Leuven, Leuven, Belgium.
6. Centre de Recherche en Cancérologie de Lyon (CRCL), Oullins, France.
7. INSERM UMR1037, Toulouse, France.
8. Josep Carreras Leukaemia Research Institute, Barcelona, Barcelona, Spain.
9. Josep Carreras Leukaemia Research Institute, Badalona, Spain.
10. CHU - Toulouse, Toulouse, France.
11. Inserm and Université de Toulouse, Toulouse, France.
12. University Hospital, Toulouse, France, Toulouse, France.
13. INSA, Toulouse, France.
14. CEA Saclay, France.
15. Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
16. Monash University, Melbourne, Australia.
17. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
18. University of Pennsylvania, Philadelphia, PA, United States.
19. University of Marseille, Marseille, France.
20. INSERM U1068, Marseille, France.
21. Institut Universitaire du Cancer de Toulouse, Toulouse Cedex 9, France.
22. INSERM, Toulouse, France.
23. IUCT-O, Toulouse, France.
24. CHU de Toulouse, Toulouse, France.
25. Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, TOULOUSE, France.
26. École Nationale Vétérinaire de Toulouse, Toulouse, France.
27. Institut Cochin, Inserm U 1016, Paris, France.
28. Université Lyon 1, Pierre Bénite, 69395, France.
29. INSERM, TOULOUSE, France.
30. KU Leuven, Leuven, Belgium.
31. INRAe, Toulouse, France.
32. INFINITY - Toulouse Institute for Infectious and Inflammatory Diseases, Toulouse, France.
33. University Hospital of Geneva, Genève, Switzerland.

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.