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.
PMID: 37012202 DOI: 10.1158/2159-8290.CD-22-0411
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.

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