| Added by | lklinares |
|---|---|
| Group name | EquipeLL |
| Item Type | Journal Article |
| Title | Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia |
| Creator | Stuani et al. |
| Author | Lucille Stuani |
| Author | Marie Sabatier |
| Author | Estelle Saland |
| Author | Guillaume Cognet |
| Author | Nathalie Poupin |
| Author | Claudie Bosc |
| Author | Florence A. Castelli |
| Author | Lara Gales |
| Author | Evgenia Turtoi |
| Author | Camille Montersino |
| Author | Thomas Farge |
| Author | Emeline Boet |
| Author | Nicolas Broin |
| Author | Clément Larrue |
| Author | Natalia Baran |
| Author | Madi Y. Cissé |
| Author | Marc Conti |
| Author | Sylvain Loric |
| Author | Tony Kaoma |
| Author | Alexis Hucteau |
| Author | Aliki Zavoriti |
| Author | Ambrine Sahal |
| Author | Pierre-Luc Mouchel |
| Author | Cédric Cassan |
| Author | Laurent Fernando |
| Author | Feng Wang |
| Author | Mohsen Hosseini |
| Author | Emeline Chu-Van |
| Author | Laurent Le Cam |
| Author | Martin Carroll |
| Author | Mary A. Selak |
| Author | Norbert Vey |
| Author | Rémy Castellano |
| Author | François Fenaille |
| Author | Andrei Turtoi |
| Author | Guillaume Cazals |
| Author | Pierre Bories |
| Author | Yves Gibon |
| Author | Brandon Nicolay |
| Author | Sébastien Ronseaux |
| Author | Joseph R. Marszalek |
| Author | Koichi Takahashi |
| Author | Courtney D. DiNardo |
| Author | Marina Konopleva |
| Author | Véra Pancaldi |
| Author | Yves Collette |
| Author | Floriant Bellvert |
| Author | Fabien Jourdan |
| Author | Laetitia K. Linares |
| Author | Christian Récher |
| Author | Jean-Charles Portais |
| Author | Jean-Emmanuel Sarry |
| Abstract | Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBP?-induced fatty acid ?-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBP? methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-? coactivator-1 PGC1? upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors. |
| Publication | The Journal of Experimental Medicine |
| Volume | 218 |
| Issue | 5 |
| Pages | e20200924 |
| Date | 2021-05-03 |
| Journal Abbr | J Exp Med |
| Language | eng |
| DOI | 10.1084/jem.20200924 |
| ISSN | 1540-9538 |
| Library Catalog | PubMed |
| Extra | PMID: 33760042 PMCID: PMC7995203 |
| Tags | Acute Disease, Aminopyridines, Animals, Cell Line, Tumor, Doxycycline, Drug Resistance, Neoplasm, Enzyme Inhibitors, Epigenesis, Genetic, Glycine, HL-60 Cells, Humans, Isocitrate Dehydrogenase, Isoenzymes, Leukemia, Myeloid, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mutation, Oxadiazoles, Piperidines, Pyridines, Triazines, Xenograft Model Antitumor Assays |
| Date Added | 2024/12/03 - 09:12:56 |
| Date Modified | 2024/12/03 - 09:12:56 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
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