APR-246 induces early cell death by ferroptosis in acute myeloid leukemia
| Title: | APR-246 induces early cell death by ferroptosis in acute myeloid leukemia |
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| Authors: | 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 |
| Source: | Haematologica, Vol 107, Iss 2 (2021) |
| Publisher Information: | Ferrata Storti Foundation, 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Diseases of the blood and blood-forming organs |
| Subject Terms: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/10139; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2020.259531 |
| Access URL: | https://doaj.org/article/450db381926d46e993daececdc3996e8 |
| Accession Number: | edsdoj.450db381926d46e993daececdc3996e8 |
| Database: | Directory of Open Access Journals |
| ISSN: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2020.259531 |
| Published in: | Haematologica |
| Language: | English |