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1. C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3 -Mutant Leukemia

Author

Marie Sabatier, Rudy Birsen, Laura Lauture, Sarah Mouche, Paolo Angelino, Jonas Dehairs, Lea Goupille, Ismael Boussaid, Mael Heiblig, Emeline Boet, Ambrine Sahal, Estelle Saland, Juliana C. Santos, Marc Armengol, Miranda Fernandez-Serrano, Thomas Farge, Guillaume Cognet, Federico Simonetta, Corentin Pignon, Antoine Graffeuil, Celine Mazzotti, Herve Avet-Loiseau, Oceane Delos, Justine Bertrand-Michel, Amelie Chedru, Vilma Dembitz, Paolo Gallipoli, Natasha S. Anstee, Sun Loo, Andrew H. Wei, Martin Carroll, Armelle Goubard, Remy Castellano, Yves Collette, Francois Vergez, Veronique Mansat-De Mas, Sarah Bertoli, Suzanne Tavitian, Muriel Picard, Christian Recher, Nathalie Bourges-Abella, Fanny Granat, Olivier Kosmider, Pierre Sujobert, Benoit Colsch, Carine Joffre, Lucille Stuani, Johannes V. Swinnen, Herve Guillou, Gael Roue, Nawad Hakim, Anne S. Dejean, Petros Tsantoulis, Clement Larrue, Didier Bouscary, Jerome Tamburini, Jean-Emmanuel Sarry, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Faculté de médecine [Genève], Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Leuven Cancer Institute [Leuven, Belgium] (LKI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Josep Carreras Leukaemia Research Institute (IJC), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Queen Mary University of London (QMUL), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Peter MacCallum Cancer Center, Perelman School of Medicine, University of Pennsylvania, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Leuven Cancer Institute (LKI), Leuven, Belgium, ToxAlim (ToxAlim), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Genève = University of Geneva (UNIGE), and 2018/Ligue Nationale de Lutte contre le Cancer C57799/A27964/Cancer Research UK (CRUK) Institut National Du Cancer (INCa)

Subjects
Oncology, [SDV]Life Sciences [q-bio]
Abstract

Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα 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/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated 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/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. Significance: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501

Published
2023

2. Supplementary Table S3 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, François Vergez, Christian Récher, Jérome Tamburini, Carine Joffre, Tony Kaoma, Francisco Azuaje, Nathalie Nicot, Jean-Charles Portais, Floriant Bellvert, Nathalie Bonnefoy, Mathilde Gotanègre, Camille Laurent, Charlotte Syrykh, Muriel Picard, Massimiliano Bardotti, Sarah Gandarillas, Latifa Jarrou, Clément Larrue, Fetta Mazed, Marie Sabatier, Lucille Stuani, Claudie Bosc, Thomas Farge, Pierre-Luc Mouchel, Mohsen Hosseini, Fabienne de Toni, Ryan Gwilliam, Estelle Saland, Marie-Laure Nicolau-Travers, Margherita Ghisi, Emeline Boet, and Nesrine Aroua

Abstract

Table S3

Published
2023

3. Supplementary Table S6 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, François Vergez, Christian Récher, Jérome Tamburini, Carine Joffre, Tony Kaoma, Francisco Azuaje, Nathalie Nicot, Jean-Charles Portais, Floriant Bellvert, Nathalie Bonnefoy, Mathilde Gotanègre, Camille Laurent, Charlotte Syrykh, Muriel Picard, Massimiliano Bardotti, Sarah Gandarillas, Latifa Jarrou, Clément Larrue, Fetta Mazed, Marie Sabatier, Lucille Stuani, Claudie Bosc, Thomas Farge, Pierre-Luc Mouchel, Mohsen Hosseini, Fabienne de Toni, Ryan Gwilliam, Estelle Saland, Marie-Laure Nicolau-Travers, Margherita Ghisi, Emeline Boet, and Nesrine Aroua

Abstract

Table S6

Published
2023

4. Supplementary Table S5 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, François Vergez, Christian Récher, Jérome Tamburini, Carine Joffre, Tony Kaoma, Francisco Azuaje, Nathalie Nicot, Jean-Charles Portais, Floriant Bellvert, Nathalie Bonnefoy, Mathilde Gotanègre, Camille Laurent, Charlotte Syrykh, Muriel Picard, Massimiliano Bardotti, Sarah Gandarillas, Latifa Jarrou, Clément Larrue, Fetta Mazed, Marie Sabatier, Lucille Stuani, Claudie Bosc, Thomas Farge, Pierre-Luc Mouchel, Mohsen Hosseini, Fabienne de Toni, Ryan Gwilliam, Estelle Saland, Marie-Laure Nicolau-Travers, Margherita Ghisi, Emeline Boet, and Nesrine Aroua

Abstract

Table S5

Published
2023

5. Supplementary Table S4 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, François Vergez, Christian Récher, Jérome Tamburini, Carine Joffre, Tony Kaoma, Francisco Azuaje, Nathalie Nicot, Jean-Charles Portais, Floriant Bellvert, Nathalie Bonnefoy, Mathilde Gotanègre, Camille Laurent, Charlotte Syrykh, Muriel Picard, Massimiliano Bardotti, Sarah Gandarillas, Latifa Jarrou, Clément Larrue, Fetta Mazed, Marie Sabatier, Lucille Stuani, Claudie Bosc, Thomas Farge, Pierre-Luc Mouchel, Mohsen Hosseini, Fabienne de Toni, Ryan Gwilliam, Estelle Saland, Marie-Laure Nicolau-Travers, Margherita Ghisi, Emeline Boet, and Nesrine Aroua

Abstract

Table S4

Published
2023

6. Supplementary Data from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini

Abstract

Supplementary Table 1 Clinical and mutational features of AML patient samples used in this study

Published
2023

7. Supplementary Figures from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini

Abstract

Supplementary Figures 1-7

Published
2023

8. Supplementary Methods from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author

Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini

Abstract

Supplementary Methods

Published
2023

9. In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

Author

Guillaume Cognet, Lucille Stuani, Thomas Farge, Mathilde Gotanègre, Maud Heuillet, Lara Gales, Amandine Rocher, Nina Lager-Lachaud, Claudie Bosc, Marie Sabatier, Estelle Saland, Ambrine Sahal, Laura Poillet-Perez, Francois Vergez, Véronique de Mas, Christian Récher, Jean-Charles Portais, Floriant Bellvert, Jean-Emmanuel Sarry, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
in vivo metabolomics, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, leukemia, prediction, metabolic niche, OxPHOS state
Abstract

Background Metabolic adaptation is a hallmark of cancer including acute myeloid leukemia (AML). Tumor microenvironment is also described as an essential support of leukemic metabolism. We explored how systemic and tissue metabolism was rewired in leukemia-bearing mice and upon chemotherapy. Methods Using AML cell line- and primary patient-derived xenograft models, we developed in vivo metabolomics to uncover the metabolic pattern of 10 tissues including plasma, bone marrow, spleen, liver, adipose tissue, lung, pancreas, kidney, heart and muscle. Results In vivo targeted mass spectrometry allowed metabolic characterization of tissues from naïve and AML-xenografted immunocompromised mice. AML xenotransplantation and cytarabine treatment induced AML cell type-dependent global changes in tissue metabolomes. Infiltration of high OxPHOS MOLM14 cells that are intrinsically chemoresistant, induced minor changes in tissue metabolomes. In contrast, low OxPHOS U937 xenograft led to major reprogramming of metabolic tissue niches for survival upon chemotherapy. Interestingly, plasma metabolite signatures could predict the oxidative phenotype of leukemic cells. Conclusion Major metabolic changes in host tissues play a crucial role in tumor xenotransplantation and define their OxPHOS state in AML. Since mitochondrial phenotype is an essential determinant of drug response in AML, plasma metabolite signatures might be novel biomarkers for patient stratification.

Published
2022

10. Abstract A24: Targeting mitochondrial metabolism following Induction Chemotherapy eradicates Acute Myeloid Leukemia at the level of Minimal Residual Disease

Author

Natalia Baran, Lina Han, Lucille Stuani, Antonio Cavazos, Laurie M. Cooper, Cassandra L. Ramage, Vinitha M. Kuruvilla, Qi Zhang, Marie Sabatier, Emeline Boet, Jason P. Gay, Ningping Feng, Lokesh Battula, Emeline Chu-Van, Florence Castelli, Martin Carrol, Sergej Konoplev, Beenu Thakral, Hagop M. Kantarjian, Naval Daver, Joseph Marszalek, Michael Andreeff, Jean-Emmanuel Sarry, and Marina Konopleva

Subjects
General Medicine
Abstract

Acute myeloid leukemia (AML) stem cells (AMLSCs) are thought to be responsible for disease initiation, chemoresistance and treatment failure. AMLSCs and residual cytarabine (AraC)-resistant AML cells (constituting minimal residual disease, MRD) were shown to be highly dependent on mitochondrial function for survival and thus are vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS) (Farge et al. Cancer Discov, 2017). Efficacy of OXPHOS inhibitor IACS-010759 was previously reported, demonstrating potent inhibition of mitochondrial complex I, OXPHOS suppression and growth inhibition of AML cells (Molina, et al. Nat Med, 2018). Here we evaluated OXPHOS dependency of AML MRD cells and determined impact of OXPHOS blockade on residual AML cells surviving standard chemotherapy (Doxorubicin/AraC, DA). Our results demonstrated that AML cell lines treated with AraC or DA induced accumulation of reactive oxygen species, mitochondrial superoxides, increased mitochondrial mass and mitochondrial membrane potential. AraC- and DA-based therapies in vitro were significantly potentiated by IACS-010759. OxPhos dependency shown as a significantly increased basal and maximal oxygen consumption rate after AraC and DA treatment, was fully inhibited by OxPhos inhibitor, leading to a total mitochondrial collapse. OxPhos inhibition in combination with DA consolidated reduction of viable cell number, induction of apoptosis and differentiation in cell lines and in AraC-resistant primary patient samples. Next, the efficacy of IACS-010759 together with DA chemotherapy was evaluated in several chemotherapy-sensitive and -resistant animal models in vivo. DA/IACS-010759 combination significantly reduced leukemia burden and significantly extended survival in OCI-AML3/Luc/GFP model and in FLT3-ITD+ AML PDX model. In the latter, IACS-010759 led to reduction of leukemia burden, and delayed leukemia recurrence when administered post completion of DA. At the single-cell level, CyTOF analysis demonstrated that this combination reduced frequency of CD34+CD38lowCD123+AML LSCs and has superior efficacy to facilitate differentiation of immature subpopulations. Furthermore, addition of IACS-010759 to DA extended survival of mice inoculated with chemoresistant PDX AML models. Finally, IACS-010759 administered during consolidation phase significantly extended mice survival compared to standard of care arm, supporting clinical utility of OXPHOS inhibitors in AML. In conclusion, our findings indicate that chemotherapy fosters mitochondrial respiration in AML, which could be abrogated by OXPHOS inhibitor at the LSCs and MRD level, in vitro and in vivo. Our data advocate for combining mitochondrial targeting strategies with chemotherapy as a part of induction and consolidation treatment for improved control of MRD, eradication of AMLSC and extended response duration. Citation Format: Natalia Baran, Lina Han, Lucille Stuani, Antonio Cavazos, Laurie M. Cooper, Cassandra L. Ramage, Vinitha M. Kuruvilla, Qi Zhang, Marie Sabatier, Emeline Boet, Jason P. Gay, Ningping Feng, Lokesh Battula, Emeline Chu-Van, Florence Castelli, Martin Carrol, Sergej Konoplev, Beenu Thakral, Hagop M. Kantarjian, Naval Daver, Joseph Marszalek, Michael Andreeff, Jean-Emmanuel Sarry, Marina Konopleva. Targeting mitochondrial metabolism following Induction Chemotherapy eradicates Acute Myeloid Leukemia at the level of Minimal Residual Disease [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A24.

Published
2023

12. Emerging metabolomic tools to study cancer metastasis

Author

Luiza Martins Nascentes Melo, Nicholas P. Lesner, Marie Sabatier, Jessalyn M. Ubellacker, and Alpaslan Tasdogan

Subjects
Cancer Research, Oncology, Neoplasms, Tumor Microenvironment, Humans, Metabolomics
Abstract

Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade. We identify advantages and disadvantages of each method and discuss how these tools and technologies will further improve our understanding of metastasis. Studies investigating the complex metabolic rewiring of different cells using state-of-the-art metabolomic technologies have the potential to reveal novel biological processes and therapeutic interventions for human cancers.

Published
2022

13. C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Author

Marie Sabatier, Rudy Birsen, Laura Lauture, Jonas Dehairs, Paolo Angelino, Sarah Mouche, Maël Heiblig, Emeline Boet, Ambrine Sahal, Estelle Saland, Thomas Farge, Guillaume Cognet, Federico Simonetta, Corentin Pignon, Antoine Graffeuil, Céline Mazzotti, Hervé Avet-Loiseau, Océane Delos, Justine Bertrand-Michel, Amélie Chedru, François Vergez, Véronique Mansat-De Mas, Sarah Bertoli, Suzanne Tavitian, Muriel Picard, Christian Récher, Olivier Kosmider, Pierre Sujobert, Benoit Colsch, Carine Joffre, Lucille Stuani, Johannes V. Swinnen, Hervé Guillou, Petros Tsantoulis, Clément Larrue, Didier Bouscary, Jérôme Tamburini, and Jean-Emmanuel Sarry

Subjects
hemic and lymphatic diseases
Abstract

While transcription factor C/AAT-enhancer binding protein α (C/EBPα) 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/EBPα 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/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application.SIGNIFICANCEThe transcription factor C/EBPα is as a master regulator of normal and leukemic myeloid differentiation. Here, we discovered that C/EBPα regulates fatty acid biosynthesis and metabolic adaptation to redox imbalance in leukemic cells. This confers a vulnerability to lipid oxidative stress to FLT3-mutant cells and supports novel therapeutic opportunities for patients.

Published
2022

14. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia

Author

Jean-Emmanuel Sarry, Thomas Farge, Eléonore Kaphan, Emeline Boet, Francois Vergez, Marie Sabatier, Jérôme Kluza, Nathalie Nicot, Yujue Wang, Andrew H. Wei, Aurélie Bousard, Noémie Gadaud, Pierre-Luc Mouchel, Ambrine Sahal, Nesrine Aroua, Ing Soo Tiong, Nathaniel Polley, Lucille Stuani, Mathilde Gotanègre, Quentin Fovez, Tony Kaoma, Laura Poillet-Perez, Claudie Bosc, Estelle Saland, Marie Tosolini, Guillaume Cognet, Rafael J. Argüello, Florian Rambow, Jean-Jacques Fournié, Christian Recher, Carine Joffre, Clément Larrue, Xiaoyang Su, Jean-Christophe Marine, Jerome Tamburini, Céline Mazzotti, Muriel Picard, Hervé Avet-Loiseau, Florence Cabon, Latifa Jarrou, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), LabEx Toucan, LabEx Toucan - Toulouse, Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Université Toulouse III Paul Sabatier - Faculté de médecine Purpan (UTPS), Université de Toulouse (UT)-Université de Toulouse (UT), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Luxembourg Institute of Health (LIH), Rutgers cancer institute of New Jersey [Newark, NJ], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), and The Alfred Hospital and Monash University - Department of Clinical Haematology - Melbourne

Subjects
Cancer Research, Combination therapy, [SDV]Life Sciences [q-bio], Cell, Oxidative phosphorylation, chemistry.chemical_compound, In vivo, hemic and lymphatic diseases, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Sulfonamides, business.industry, Venetoclax, Cytarabine, Myeloid leukemia, Pyruvate dehydrogenase complex, Bridged Bicyclo Compounds, Heterocyclic, carbohydrates (lipids), Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, chemistry, Cancer research, Azacitidine, business, medicine.drug
Abstract

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a ‘MitoScore’ signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies. Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.

Published
2021

15. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Author

Pierre Bories, Sonia Zaghdoudi, Jean-Emmanuel Sarry, Florence Castelli, Héléna Boutzen, Alexis Hucteau, Sarah Bertoli, Marie Sabatier, Ambrine Sahal, Laura Lauture, Thomas Farge, Vera Pancaldi, Emeline Chu-Van, Lucille Stuani, Emeline Boet, Nathaniel Polley, Christian Récher, Nathan Guiraud, Guillaume Cognet, Estelle Saland, and Véronique Mansat-De Mas

Subjects
IDH, business.industry, Mutant, CEBPα, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, vitamin D, biology_other, differentiation, Calcitriol receptor, Article, Isocitrate dehydrogenase, AML, Cell culture, hemic and lymphatic diseases, CEBPA, Vitamin D and neurology, Cancer research, Medicine, Stem cell, ATRA, business, neoplasms, RC254-282, VDR
Abstract

Simple Summary Around 15% of acute myeloid leukemia (AML) patients harbor mutations in isocitrate dehydrogenases (IDH), which lead to the production of the oncometabolite 2-hydroxyglutarate (2-HG). Inhibitors of mutant IDH enzymes and their 2-HG production have been approved by the FDA to be used in patients. However, 60% of IDH mutant AML patients do not respond to these inhibitors or develop mechanisms of resistance, leading to relapse. Among these mechanisms, some produce a 2-HG rebound. Alternative therapies exploiting the 2-HG-dependent molecular effects could therefore be of clinical interest. In this study, we demonstrate that 2-HG specifically activates vitamin D receptor (VDR) in IDH mutant AML cells leading to increased sensitivity to the combination of vitamin D (or VDR agonist) and all-trans retinoic acid and revealing a new therapeutic approach that can be readily applied to AML patients in this subgroup. Abstract Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.

Published
2021
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