APR-246 induces early cell death by ferroptosis in acute myeloid leukemia
Rudy Birsen,
Clement Larrue,
Justine Decroocq,
Natacha Johnson,
Nathan Guiraud,
Mathilde Gotanegre,
Lilia Cantero-Aguilar,
Eric Grignano,
Tony Huynh,
Michaela Fontenay,
Olivier Kosmider,
Patrick Mayeux,
Nicolas Chapuis,
Jean Emmanuel Sarry,
Jerome Tamburini,
Didier Bouscary
Affiliations
Rudy Birsen
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie clinique, Hôpital Cochin, Paris
Clement Larrue
Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva
Justine Decroocq
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie clinique, Hôpital Cochin, Paris
Natacha Johnson
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris
Nathan Guiraud
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France; University of Toulouse, F-31077 Toulouse
Mathilde Gotanegre
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France; University of Toulouse, F-31077 Toulouse
Lilia Cantero-Aguilar
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris
Eric Grignano
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris
Tony Huynh
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris
Michaela Fontenay
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie biologique, Hôpital Cochin, Paris
Olivier Kosmider
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie biologique, Hôpital Cochin, Paris
Patrick Mayeux
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris
Nicolas Chapuis
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie biologique, Hôpital Cochin, Paris
Jean Emmanuel Sarry
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Equipe Labellisée LIGUE 2018, F-31037 Toulouse
Jerome Tamburini
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie clinique, Hôpital Cochin, Paris, France; Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva
Didier Bouscary
Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d’Hématologie clinique, Hôpital Cochin, Paris
APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.
