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Acute Myeloid Leukemia
APR-246 induces early cell death by ferroptosis in acute myeloid leukemia
Rudy Birsen,1,2 Clement Larrue,3 Justine Decroocq,1,2 Natacha Johnson,1 Nathan Guiraud,4,5 Mathilde Gotanegre,4,5 Lilia Cantero-Aguilar,1
Eric Grignano,1 Tony Huynh,1 Michaela Fontenay,1,6 Olivier Kosmider,1,6 Patrick Mayeux,1 Nicolas Chapuis,1,6 Jean Emmanuel Sarry,4
Jerome Tamburini,1,2,3 and Didier Bouscary1,2
1Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; 2Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Service d’Hématologie Clinique, Hôpital Cochin, Paris, France; 3Translational Research Center in Onco-Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; 4Centre de Recherches en Cancérologie de Toulouse, UMR1037, INSERM, Equipe Labellisée LIGUE 2018, Toulouse, France; 5Université de Toulouse, Institut National des Sciences Appliquées de Toulouse, INSERM, Toulouse, France and 6Assistance Publique- Hôpitaux de Paris, Centre-Université de Paris, Service d’Hématologie Biologique, Hôpital Cochin, Paris, France
ABSTRACT
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 deter- minant 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.
Introduction
Acute myeloid leukemias (AML) are highly heterogeneous diseases with a con- stant activation of oncogenic signaling.1 Recent years have witnessed major break- throughs in their treatment with the approval of midostaurin, venetoclax and IDH mutant inhibitors.2-5 However, AML has a poor prognosis and there is still an urgent need for new treatments. APR-246, also known as PRIMA-1MET, is a promising new therapeutic agent that targets TP53 mutated cancers.6-8 This compound is being evaluated in AML and myelodysplastic syndromes (MDS) with TP53 muta- tions and appears to be highly effective against this poor prognosis disease.8-11 Mechanistically, APR-246 is converted to a reactive product (methylene quinuclidi- none, MQ) that reacts with nucleophiles and thus alkylates thiol groups in proteins.12 APR-246 reactivates the transcriptional activity of p53 mutants by facil- itating their binding to DNA target sites. Specific cysteines in the core domain of mutant p53 proteins are critical targets for their reactivation by APR-246/MQ.13 APR-246 also triggers p53-independent cell death mechanisms.14,15 Accordingly, using esophageal cancer as a model, it has been shown that APR-246 causes a decrease in glutathione (GSH) content resulting in an increased amount of reactive oxygen species (ROS) and of lipid peroxides in particular.16 In this report, we inves- tigated the mechanisms of cell death induced by APR-246 in AML and we demon- strated that early cell death in AML is due to ferroptosis induction.
Ferrata Storti Foundation
Haematologica 2022 Volume 107(2):403-416
Correspondence:
RUDY BIRSEN
rudy.birsen@inserm.fr
DIDIER BOUSCARY
didier.bouscary@aphp.fr
Received: May 18, 2020. Accepted: December 28, 2020. Pre-published: January 7, 2021.
https://doi.org/10.3324/haematol.2020.259531 ©2022 Ferrata Storti Foundation
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