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2. CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation

Author

Lawson, Hannah, van de Lagemaat, Louie N., Barile, Melania, Tavosanis, Andrea, Durko, Jozef, Villacreces, Arnaud, Bellani, Aarushi, Mapperley, Christopher, Georges, Elise, Martins-Costa, Catarina, Sepulveda, Catarina, Allen, Lewis, Campos, Joana, Campbell, Kirsteen J., O'Carroll, Dónal, Göttgens, Berthold, Cory, Suzanne, Rodrigues, Neil P., Guitart, Amelie V., and Kranc, Kamil R.

Published
2021
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6. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author

Mogilenko, Denis A., Haas, Joel T., L’homme, Laurent, Fleury, Sébastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Hélène, Gheeraert, Celine, Melchior, Aurelie, Dewas, Cédric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sébastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria P., Paget, Christophe, Janssens, Sophie, Staumont-Sallé, Delphine, Aksoy, Ezra, Staels, Bart, and Dombrowicz, David

Published
2019
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7. Expression of miRNA-210 in human bone marrow-derived mesenchymal stromal cells under oxygen deprivation

Author

Lončarić Darija, Stanković Biljana, Ghousein Amani, Vreća Miša, Spasovski Vesna, Villacreces Arnaud, Debeissat Christelle, Grosset Christophe F., Ivanović Zoran, and Pavlović Sonja

Subjects
mesenchymal stromal cells, oxygen deprivation, miRNA-210, HIF-1α, HIF-2α, Biology (General), QH301-705.5
Abstract

A major limitation in the development of efficient clinical protocols for mesenchymal stromal cell (MStroC)-based tissue regeneration therapy is the low retention and survival of MStroC in injured tissue after therapeutic administration. Low oxygen concentration preconditioning (LOP) during ex vivo cultivation of MStroC, as a method for mimicking oxygenation in their physiological microenvironment, has been shown to be beneficial in clinical trials using MStroC. Introducing hypoxia-mimicking molecules into MStroC during cultivation could be an advantageous LOP strategy. MicroRNA (miRNA) drugs are good candidates for this approach. Analysis of the expression of miRNA-210 in human bone marrow-derived MStroC in conditions of acute and extended hypoxia (24 to 72 h) was performed using RT-qPCR methodology. HIF-1α and HIF-2α gene knockdown cell lines were generated using lentiviral transduction of short hairpin RNA (shRNA) in order to examine whether miRNA-210 expression is regulated by transcription factor HIF-1 and/or HIF-2. We detected a significant increase in miRNA-210 expression in hypoxic conditions at time points of 24, 48 and 72 h (p

Published
2019
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9. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

Author

Dupont, Marine, primary, Huart, Mathilde, additional, Lauvinerie, Claire, additional, Bidet, Audrey, additional, Guitart, Amélie Valérie, additional, Villacreces, Arnaud, additional, Vigon, Isabelle, additional, Desplat, Vanessa, additional, El Habhab, Ali, additional, Pigneux, Arnaud, additional, Ivanovic, Zoran, additional, Brunet De la Grange, Philippe, additional, Dumas, Pierre-Yves, additional, and Pasquet, Jean-Max, additional

Published
2022
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13. Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3-ITD Acute Myeloid Leukemia

Author

Dumas, Pierre-Yves, primary, Villacreces, Arnaud, additional, Guitart, Amélie V., additional, El-habhab, Ali, additional, Massara, Layal, additional, Mansier, Olivier, additional, Bidet, Audrey, additional, Martineau, Delphine, additional, Fernandez, Solene, additional, Leguay, Thibaut, additional, Pigneux, Arnaud, additional, Vigon, Isabelle, additional, Pasquet, Jean-Max, additional, and Desplat, Vanessa, additional

Published
2021
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15. alpha-Tocopherol Acetate Attenuates Mitochondrial Oxygen Consumption and Maintains Primitive Cells within Mesenchymal Stromal Cell Population

Author

Loncarić, Darija, Rodriguez, Laura, Debeissat, Christelle, Touya, Nicolas, Labat, Veronique, Villacreces, Arnaud, Bouzier-Sore, Anne-Karine, Pasquet, Jean-Max, de la Grange, Philippe Brunet, Vlaski-Lafarge, Marija, Pavlović, Sonja, Ivanović, Zoran, Loncarić, Darija, Rodriguez, Laura, Debeissat, Christelle, Touya, Nicolas, Labat, Veronique, Villacreces, Arnaud, Bouzier-Sore, Anne-Karine, Pasquet, Jean-Max, de la Grange, Philippe Brunet, Vlaski-Lafarge, Marija, Pavlović, Sonja, and Ivanović, Zoran

Abstract

We present here the data showing, in standard cultures exposed to atmospheric O-2 concentration, that alpha-tocopherol acetate (alpha-TOA) has a positive impact on primitive cells inside mesenchymal stromal cell (MstroC) population, by maintaining their proliferative capacity. alpha-TOA decreases the O-2 consumption rate of MStroC probably by impacting respiratory chain complex II activity. This action, however, is not associated with a compensatory increase in glycolysis activity, in spite of the fact that the degradation of HIF-1 alpha was decreased in presence of alpha-TOA. This is in line with a moderate enhancement of mtROS upon alpha-TOA treatment. However, the absence of glycolysis stimulation implies the inactivity of HIF-1 alpha which might - if it were active - be related to the maintenance of stemness. It should be stressed that alpha-TOA might act directly on the gene expression as well as the mtROS themselves, which remains to be elucidated.

Published
2021

16. Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Author

Paris, Jasmin, Morgan, Marcos, Campos, Joana, Spencer, Gary J., Shmakova, Alena, Ivanova, Ivayla, Mapperley, Christopher, Lawson, Hannah, Wotherspoon, David A., Sepulveda, Catarina, Vukovic, Milica, Allen, Lewis, Sarapuu, Annika, Tavosanis, Andrea, Guitart, Amelie V., Villacreces, Arnaud, Much, Christian, Choe, Junho, Azar, Ali, van de Lagemaat, Louie N., Vernimmen, Douglas, Nehme, Ali, Mazurier, Frederic, Somervaille, Tim C.P., Gregory, Richard I., O’Carroll, Dónal, and Kranc, Kamil R.

Published
2019
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17. Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia

Author

Crinier, Adeline, primary, Dumas, Pierre-Yves, additional, Escalière, Bertrand, additional, Piperoglou, Christelle, additional, Gil, Laurine, additional, Villacreces, Arnaud, additional, Vély, Frédéric, additional, Ivanovic, Zoran, additional, Milpied, Pierre, additional, Narni-Mancinelli, Émilie, additional, and Vivier, Éric, additional

Published
2020
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19. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL

Author

Dumas, Pierre-Yves, Naudin, Cécile, Martin-Lannerée, Séverine, Izac, Brigitte, Casetti, Luana, Mansier, Olivier, Rousseau, Benoît, Artus, Alexandre, Dufossée, Mélody, Giese, Alban, Dubus, Pierre, Pigneux, Arnaud, Praloran, Vincent, Bidet, Audrey, Villacreces, Arnaud, Guitart, Amélie, Milpied, Noël, Kosmider, Olivier, Vigon, Isabelle, Desplat, Vanessa, Dusanter-Fourt, Isabelle, Pasquet, Jean-Max, CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris., Service de Biologie des Tumeurs and Laboratoire d'Hématologie Biologique, Centre Hospitalo-Universitaire CHU Bordeaux, F-33000, Bordeaux., Service Commun des Animaleries, Animalerie A2, Université de Bordeaux, Bordeaux., TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-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), Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Paris, France., Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris isabelle.dusanter@inserm.fr., and Vigon, Isabelle

Subjects
Acute Myeloid Leukemia, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Phenylurea Compounds, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Article, Up-Regulation, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, fms-Like Tyrosine Kinase 3, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, embryonic structures, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], STAT5 Transcription Factor, Tumor Microenvironment, Humans, Benzothiazoles, Hypoxia, ComputingMilieux_MISCELLANEOUS
Abstract

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

Published
2019
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20. Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Author

Fernandez, Solène, Desplat, Vanessa, Villacreces, Arnaud, Guitart, Amélie V., Milpied, Noël, Pigneux, Arnaud, Vigon, Isabelle, Pasquet, Jean-Max, and Dumas, Pierre-Yves

Subjects
Clinical Trials as Topic, Proteome, Gene Expression Regulation, Leukemic, tyrosine kinase, Antineoplastic Agents, Review, Protein-Tyrosine Kinases, acute myeloid leukemia, targeted therapy, lcsh:Chemistry, Leukemia, Myeloid, Acute, Treatment Outcome, lcsh:Biology (General), lcsh:QD1-999, hemic and lymphatic diseases, inhibitors, Biomarkers, Tumor, Animals, Humans, Molecular Targeted Therapy, Transcriptome, Protein Kinase Inhibitors, lcsh:QH301-705.5, Signal Transduction
Abstract

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

Published
2019

21. Metabolic and innate immune cues merge into a specific inflammatory response via unfolded proteinresponse (UPR)

Author

Mogilenko, Denis, Haas, Joël, L'Homme, Laurent, Fleury, Sébastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Hélène, Gheeraert, Céline, Melchior, Aurélie, Dewas, Cédric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sébastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria, Paget, Christophe, Janssens, Sophie, Staumont-Sallé, Delphine, Aksoy, Ezra, Staels, Bart, Dombrowicz, David, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), 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 National de la Recherche Scientifique (CNRS), Fujii Memorial Institute of Medical Sciences [Tokushima, Japan] (Institute of Advanced Medical Sciences), Tokushima University, Department of Hematology [Linköping, Sweden] (Institute for Clinical and Experimental Medicine), Linköping University (LIU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Centre for Haemato-Oncology [London, UK] (Barts Cancer Institute), Queen Mary University of London (QMUL), Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium], VIB-KU Leuven Center for Brain & Disease Research [Leuven, Belgium], Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium] (VIB-CCB), Department of Oncology [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), MOdel for Data Analysis and Learning (MODAL), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)-Université de Lille, Sciences et Technologies, University of Florida [Gainesville] (UF), Unit of Immunoregulation and Mucosal Immunology [Ghent, Belgium], VIB Inflammation Research Center [Ghent, Belgium], Hannover Medical School [Hannover] (MHH), The William Harvey Research Institute [London, UK] (NIHR Barts Biomedical Research Centre), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), ER Stress and Inflammation [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Département de Dermatologie [CHRU Lille], Centre for Biochemical Pharmacology [London, UK] (William Harvey Research Institute), This work was supported in part by grants from ANR and the European Union (EGID ANR-10-LABX-46 to B.S. and D.D. and ANR-17-CE15-0030-02 to B.V.), a National Psoriasis Foundation (USA) Early Career Research Grant (to D.A.M.), an EMBO Long-Term Fellowship (to J.T.H.), an MRC grant (MR/M023230/1 to E.A.), and CRUK grants (C29967/A14633 and C29967/A26787 to K.K.). B.S. is recipient of an ERC advanced grant (ERC-2016-AdG-694717)., We thank members of the Bart Staels lab for help with experiments, Jean-Claude Sirard (Institut Pasteur de Lille, France), Juan R. Cubillos-Ruiz and Laurie H. Glimcher (Weill Cornell Medical College, New York, USA), Eik Hoffmann (Institut Pasteur de Lille, France) for mice, and Morten Danielsen and Lea Johnsen (MS-Omics, Copenhagen, Denmark) for assistance with LC-MS and GC-MS., 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), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE15-0030,MetaTreg,Métabolisme cellulaire des Treg dans le controle des maladies inflammatoires chroniques(2017), Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille), and Dupuis, Christine

Subjects
mtROS, [SDV.IMM] Life Sciences [q-bio]/Immunology, hexokinase, UPR, psoriasis, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, glycolysis, fatty acids, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, IL-23, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, metabolic reprogramming, [SDV.IMM]Life Sciences [q-bio]/Immunology, dendritic cells, innate immunity, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Erratum in : Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. [Cell. 2019]; International audience; Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-likereceptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatorysignals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect theimmune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC)are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-inducedhexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changesenhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded proteinresponse (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly,chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innateimmunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Published
2019
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22. STAT5-and hypoxia-dependent upregulation of AXL

Author

DUMAS, Pierre-Yves, NAUDIN, Cécile, MARTIN-LANNERÉE, Séverine, IZAC, Brigitte, CASETTI, Luana, MANSIER, Olivier, ROUSSEAU, Benoît, ARTUS, Alexandre, DUFOSSÉE, Mélody, GIESE, Alban, DUBUS, Pierre, PIGNEUX, Arnaud, PRALORAN, Vincent, BIDET, Audrey, VILLACRECES, Arnaud, GUITART, Amélie, MILPIED, Noël, KOSMIDER, Olivier, VIGON, Isabelle, DESPLAT, Vanessa, DUSANTER-FOURT, Isabelle, and PASQUET, Jean-Max

Subjects
Article RECHERCHE
Published
2019

23. Midostaurin resistance in FLT3-ITD acute myeloblastic leukemia: Fonctional genomic screening by Crispr-Cas9

Author

Fernandez, Solène, Lewis, Matthieu, Guitart, Amélie, Massara*, Layal, Fabres, Clémentine, Villacreces, Arnaud, Desplat, Vanessa, Turcq, Béatrice, Dumas, Pierre‐yves, Pasquet, Jean-Max, Vigon, Isabelle, and Vigon, Isabelle

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Published
2019

24. Expression of miRNA-210 in human bone marrow-derived mesenchymal stromal cells under oxygen deprivation

Author

Loncarić, Darija, Stanković, Biljana, Ghousein, Amani, Vreca, Misa, Spasovski, Vesna, Villacreces, Arnaud, Debeissat, Christelle, Grosset, Christophe F., Ivanović, Zoran, Pavlović, Sonja, Loncarić, Darija, Stanković, Biljana, Ghousein, Amani, Vreca, Misa, Spasovski, Vesna, Villacreces, Arnaud, Debeissat, Christelle, Grosset, Christophe F., Ivanović, Zoran, and Pavlović, Sonja

Abstract

A major limitation in the development of efficient clinical protocols for mesenchymal stromal cell (MStroC)-based tissue regeneration therapy is the low retention and survival of MStroC in injured tissue after therapeutic administration. Low oxygen concentration preconditioning (LOP) during ex vivo cultivation of MStroC, as a method for mimicking oxygenation in their physiological microenvironment, has been shown to be beneficial in clinical trials using MStroC. Introducing hypoxia-mimicking molecules into MStroC during cultivation could be an advantageous LOP strategy. MicroRNA (miRNA) drugs are good candidates for this approach. Analysis of the expression of miRNA-210 in human bone marrow-derived MStroC in conditions of acute and extended hypoxia (24 to 72 h) was performed using RT-qPCR methodology. HIF-1 alpha and HIF-2 alpha gene knockdown cell lines were generated using lentiviral transduction of short hairpin RNA (shRNA) in order to examine whether miRNA-210 expression is regulated by transcription factor HIF-1 and/or HIF-2. We detected a significant increase in miRNA-210 expression in hypoxic conditions at time points of 24, 48 and 72 h (p lt 0.05). Knocking down of HIF-1 alpha and HIF-2 alpha genes indicated involvement of both transcription factors in the elevation of miRNA-210 expression. These results point to miRNA-210 as a good candidate for a hypoxia-mimicking molecule in LOP strategy.

Published
2019

25. Additional file 3: of MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms

Author

Pierre-Yves Dumas, Mansier, Olivier, Prouzet-Mauleon, Valerie, Koya, Junji, Villacreces, Arnaud, Grange, Philippe Brunet De La, Paz, Damien Luque, Bidet, Audrey, Jean-Max Pasquet, Praloran, Vincent, Salin, Franck, Kurokawa, Mineo, François-Xavier Mahon, Cardinaud, Bruno, and Lippert, Eric

Abstract

Figure S1. (A) Expression of HOXB4 in OCI-AML3 according to treatment by 5-aza-2’deoxycytidine (DEOX), valproic acid (VPA), and retinoic acid (RA). OCI-AML3 were treated with 2 μM DEOX and/or 1 mM VPA for 48 h and/or 2 μM RA for 4 h. qRT-PCR measured the relative expression of HOXB4 with TUBA1C and RPLP0 both used as control genes. The graphs show fold induction of gene expression by treatment over DMSO control with mean ± SEM (n = 3). *, p

Published
2018
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27. Additional file 2: of MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms

Author

Pierre-Yves Dumas, Mansier, Olivier, Prouzet-Mauleon, Valerie, Koya, Junji, Villacreces, Arnaud, Grange, Philippe Brunet De La, Paz, Damien Luque, Bidet, Audrey, Jean-Max Pasquet, Praloran, Vincent, Salin, Franck, Kurokawa, Mineo, François-Xavier Mahon, Cardinaud, Bruno, and Lippert, Eric

Abstract

Table S1. Characteristics of patients with atypical myeloproliferative neoplasms (n = 18). Table S2. Characteristics of patients with hematological malignancies (n = 39). (DOC 136 kb)

Published
2018
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28. Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence

Author

Ianniciello, Angela, Dumas, Pierre-Yves, Drullion, Claire, Guitart, Amélie, Villacreces, Arnaud, Peytour, Yan, Chevaleyre, Jean, de La Grange, Philippe Brunet, Vigon, Isabelle, Desplat, Vanessa, Priault, Muriel, Sbarba, Persio Dello, Ivanovic, Zoran, Mahon, Francois-Xavier, Pasquet, Jean-Max, Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1035 BMGIC, Université de Bordeaux, 33076 Bordeaux Cedex, France., Etablissement Français du Sang Aquitaine-Limousin, 33075 Bordeaux, France., Cellules souches hématopoïétiques normales et leucémiques, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR CNRS 5095, I.B.G.C, Université de Bordeaux, 33077 Bordeaux Cedex, France., Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, 50134 Firenze, Italia., INSERM U1218, Institut Bergonié, 33076 Bordeaux, France., Vigon, Isabelle, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Department of Experimental and Clinical Biomedical Sciences [Firenze] (UniFI), and Università degli Studi di Firenze = University of Florence (UniFI)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Autophagy, Chronic myeloid leukemia, Stem cell, Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2017
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30. Fumarate hydratase is a critical regulator of hematopoietic stem cell functions

Author

Guitart, Amelie V, Panagopoulou, Theano I, Villacreces, Arnaud, Vukovic, Milica, Sepulveda, Catarina, Allen, Lewis, Carter, Roderick N, Lagemaat, Louie N van de, Morgan, Marcos, Giles, Peter, Sas, Zuzanna, Gonzalez, Marta Vila, Lawson, Hannah, Paris, Jasmin, Edwards-Hicks, Joy, Schaak, Katrin, Subramani, Chithra, Gezer, Deniz, Armesilla-Diaz, Alejandro, Wills, Jimi Carlo, Easterbrook, Aaron, Coman, David, Wai, Chi, So, Eric, O'Carroll, Donal, Vernimmen, Douglas, Rodrigues, Neil, Pollard, Patrick J, Morton, Nicholas M, Finch, Andrew, and Kranc, Kamil R

Subjects
RC0254, QH301, QH426
Abstract

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation.

Published
2017

31. Fumarate hydratase is a critical metabolic regulator of haematopoietic stem cell functions

Author

Guitart, Amelie, Panagopoulou, Theoni, Villacreces, Arnaud, Vukovic, Milica, Sepulveda, Catarina, Allen, Lewis, Carter, Roderick N., van de Lagemaat, Louie, Morgan, Marcos, Giles, Peter, Sas, Zuzanna, Vila Gonzalez, Marta, Lawson, Hannah, Paris, Jasmin, Edward-Hicks, Joy, Schaak, Katrin, Subramani, Chithra, Gezer, Deniz, Armesilla-Diaz, Alejandro, Bukowski-Wills, Jimi, Easterbrook, Aaron, Coman, David, So, Chi Wai Eric, O'Carroll, Donal, Vernimmen, Douglas, Rodrigues, Neil P, Pollard, Patrick J, Morton, Nicholas M., Finch, Andrew, and Kranc, Kamil R.

Abstract

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation.

Published
2017
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32. L'hypoxie contribue à la quiescence et la chimiorésistance des cellules initiatrices de leucémie aigüe lymphoblastique

Author

Villacreces, Arnaud, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux, and Vincent Praloran

Subjects
Hypoxie, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Relapse, Quiescence, Rechute, Chimiorésistance, Acute Lymphoblastic Leukemia, Hypoxia, Chemoresistance, Leukemic Stem Cells, Leucémie Aigüe Lymphoblastique, Cellules souches Leucémiques
Abstract

Our group showed that severe hypoxia (0.1% O2) induces G0 cell-cycle-arrest of human CD34+ cells and of murine FDCP-mix Cells. Few studies explored the existence of quiescent Leukemia Initiating Cells (LIC) in ALL and their role in primary chemoresistance and relapses. Our project is focused on the effect of very low O2 concentrations in the maintenance of quiescent LIC in ALL, that could be responsible of a percentage of relapses. Indeed in bone marrow niches, where hematopoietic stem cells and probably LIC are located, the O2 concentrations are below 0.1%.In the present study we used the NALM-6 ALL cell line to explore the effects of culture at 0.1% O2 on their survival, cell cycle and chemoresistance. Our results evidence that a 7 days culture of NALM-6 cells at 0.1% O2: - inhibits their proliferation without major cell death; - reveals a restricted LIC population of quiescent and chemoresistant LIC; - maintains quiescent chemoresistant LIC that induce leukemia when injected in immunodeficient mice. We investigated the relationships between severe hypoxia and some characteristics of ALL primary cells obtained from patients: existence and role of quiescent chemoresistant LICs in ALL relapses; location of these residual cells inside the bone marrow of engrafted mice. Our results suggest that some ALL relapses could be due to the long term persistence of “quiescent / dormant” LIC in hypoxic bone marrow niches. This model is of interest for exploring the in vitro and in vivo (xenograft) mechanisms of chemoresistance in ALL and the role of the bone marrow environment in this phenomenon.; Notre groupe a montré que l’hypoxie sévère (0.1% O2) induit un arrêt du cycle cellulaire en G0 des cellules humaines CD34+ et des cellules murines FDCP mix. Peu d’études ont exploré l’existence de Cellules Initiatrices de Leucémie (CIL) dans les LAL et leur rôle dans les rechutes. Notre projet s’est focalisé sur l’effet de l’hypoxie sévère sur la quiescence des CIL dans les LAL, qui pourrait être responsable d’un pourcentage de rechutes. En effet dans la niche hématopoïétique, ou sont localisées les Cellules souches hématopoïétiques et probablement les CIL, la concentration d’oxygène avoisinerait 0,1%.Nous avons utilisé la lignée de LAL NALM6 pour explorer les effets de l’hypoxie sévère sur leur survie, leur cycle cellulaire et leur chimiorésistance. Nos résultats ont mis en évidence qu’une culture à 0.1% O2 durant 7 jours de la lignée NALM6: - inhibe leur prolifération sans surmortalité, - révèle une population restreinte de CIL quiescentes et chimiorésistantes capables d’induire une leucémie dans des souris. Nous avons recherché les relations entre l’hypoxie sévère et quelques caractéristiques des cellules primaires de patients atteints de LAL : existence et rôle de CIL résistantes à l’hypoxie et aux agents thérapeutiques conventionnels des LAL ; localisation de ces cellules résiduelles dans la moelle osseuse des souris xénogreffées. Nos résultats suggèrent que certaines rechutes de LAL pourraient être dues à la persistance à long terme de « quiescent/dormant » CIL dans les niches hypoxiques de la moelle osseuse. Ce modèle est intéressant pour explorer les mécanismes in vitro et in vivo de chimiorésistance dans les LAL et le rôle de l’environnement dans ce phénomène.

Published
2014

33. Steady state peripheral blood provides cells with functional and metabolic characteristics of real hematopoietic stem cells

Author

Bourdieu, Antonin, primary, Avalon, Maryse, additional, Lapostolle, Véronique, additional, Ismail, Sadek, additional, Mombled, Margaux, additional, Debeissat, Christelle, additional, Guérinet, Marianne, additional, Duchez, Pascale, additional, Chevaleyre, Jean, additional, Vlaski‐Lafarge, Marija, additional, Villacreces, Arnaud, additional, Praloran, Vincent, additional, Ivanovic, Zoran, additional, and Brunet de la Grange, Philippe, additional

Published
2017
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34. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions

Author

Guitart, Amelie V., primary, Panagopoulou, Theano I., additional, Villacreces, Arnaud, additional, Vukovic, Milica, additional, Sepulveda, Catarina, additional, Allen, Lewis, additional, Carter, Roderick N., additional, van de Lagemaat, Louie N., additional, Morgan, Marcos, additional, Giles, Peter, additional, Sas, Zuzanna, additional, Gonzalez, Marta Vila, additional, Lawson, Hannah, additional, Paris, Jasmin, additional, Edwards-Hicks, Joy, additional, Schaak, Katrin, additional, Subramani, Chithra, additional, Gezer, Deniz, additional, Armesilla-Diaz, Alejandro, additional, Wills, Jimi, additional, Easterbrook, Aaron, additional, Coman, David, additional, So, Chi Wai Eric, additional, O’Carroll, Donal, additional, Vernimmen, Douglas, additional, Rodrigues, Neil P., additional, Pollard, Patrick J., additional, Morton, Nicholas M., additional, Finch, Andrew, additional, and Kranc, Kamil R., additional

Published
2017
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36. This title is unavailable for guests, please login to see more information.

Author

Khairallah, Camille, Netzer, Sonia, Villacreces, Arnaud, Juzan, Marina, Rousseau, Benoît, Dulanto Magallanes, Sara Adriana, Giese, Alban, Costet, Pierre, Praloran, Vincent, Moreau, Jean François, Dubus, Pierre, Vermijlen, David, Dechanet-Merville, Julie, Capone, Myriam, Khairallah, Camille, Netzer, Sonia, Villacreces, Arnaud, Juzan, Marina, Rousseau, Benoît, Dulanto Magallanes, Sara Adriana, Giese, Alban, Costet, Pierre, Praloran, Vincent, Moreau, Jean François, Dubus, Pierre, Vermijlen, David, Dechanet-Merville, Julie, and Capone, Myriam

Abstract

info:eu-repo/semantics/published

Published
2015

37. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Author

Vukovic, Milica, primary, Guitart, Amelie V., additional, Sepulveda, Catarina, additional, Villacreces, Arnaud, additional, O'Duibhir, Eoghan, additional, Panagopoulou, Theano I., additional, Ivens, Alasdair, additional, Menendez-Gonzalez, Juan, additional, Iglesias, Juan Manuel, additional, Allen, Lewis, additional, Glykofrydis, Fokion, additional, Subramani, Chithra, additional, Armesilla-Diaz, Alejandro, additional, Post, Annemarie E.M., additional, Schaak, Katrin, additional, Gezer, Deniz, additional, So, Chi Wai Eric, additional, Holyoake, Tessa L., additional, Wood, Andrew, additional, O'Carroll, Dónal, additional, Ratcliffe, Peter J., additional, and Kranc, Kamil R., additional

Published
2015
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38. Steady state peripheral blood provides cells with functional and metabolic characteristics of real hematopoietic stem cells.

Author

Bourdieu, Antonin, Avalon, Maryse, Lapostolle, Véronique, Ismail, Sadek, Mombled, Margaux, Debeissat, Christelle, Guérinet, Marianne, Duchez, Pascale, Chevaleyre, Jean, Vlaski-Lafarge, Marija, Villacreces, Arnaud, Praloran, Vincent, Ivanovic, Zoran, and de la Grange, Philippe Brunet

Subjects
HEMATOPOIETIC stem cells, CORD blood, CELL proliferation, XENOGRAFTS, HYPOXIA-inducible factor 1
Abstract

Hematopoietic stem cells (HSCs), which are located in the bone marrow, also circulate in cord and peripheral blood. Despite high availability, HSCs from steady state peripheral blood (SSPB) are little known and not used for research or cell therapy. We thus aimed to characterize and select HSCs from SSPB by a direct approach with a view to delineating their main functional and metabolic properties and the mechanisms responsible for their maintenance. We chose to work on Side Population (SP) cells which are highly enriched in HSCs in mouse, human bone marrow, and cord blood. However, no SP cells from SSBP have as yet been characterized. Here we showed that SP cells from SSPB exhibited a higher proliferative capacity and generated more clonogenic progenitors than non-SP cells in vitro. Furthermore, xenotransplantation studies on immunodeficient mice demonstrated that SP cells are up to 45 times more enriched in cells with engraftment capacity than non-SP cells. From a cell regulation point of view, we showed that SP activity depended on O2 concentrations close to those found in HSC niches, an effect which is dependent on both hypoxia-induced factors HIF-1α and HIF-2α. Moreover SP cells displayed a reduced mitochondrial mass and, in particular, a lower mitochondrial activity compared to non-SP cells, while they exhibited a similar level of glucose incorporation. These results provided evidence that SP cells from SSPB displayed properties of very primitive cells and HSC, thus rendering them an interesting model for research and cell therapy. [ABSTRACT FROM AUTHOR]

Published
2018
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39. γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV)

Author

Khairallah, Camille, primary, Netzer, Sonia, additional, Villacreces, Arnaud, additional, Juzan, Marina, additional, Rousseau, Benoît, additional, Dulanto, Sara, additional, Giese, Alban, additional, Costet, Pierre, additional, Praloran, Vincent, additional, Moreau, Jean-François, additional, Dubus, Pierre, additional, Vermijlen, David, additional, Déchanet-Merville, Julie, additional, and Capone, Myriam, additional

Published
2015
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42. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.

Author

Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, and Pasquet JM

Subjects
Cell Hypoxia, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Leukemic drug effects, Humans, K562 Cells, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, STAT5 Transcription Factor genetics, Up-Regulation drug effects, fms-Like Tyrosine Kinase 3 genetics, Axl Receptor Tyrosine Kinase, Benzothiazoles pharmacology, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute metabolism, Phenylurea Compounds pharmacology, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis, STAT5 Transcription Factor metabolism, Tumor Microenvironment, fms-Like Tyrosine Kinase 3 metabolism
Abstract

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones., (Copyright© 2019 Ferrata Storti Foundation.)

Published
2019
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43. Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence.

Author

Ianniciello A, Dumas PY, Drullion C, Guitart A, Villacreces A, Peytour Y, Chevaleyre J, Brunet de la Grange P, Vigon I, Desplat V, Priault M, Sbarba PD, Ivanovic Z, Mahon FX, and Pasquet JM

Abstract

Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O 2 for 7 days) followed back by non-restricted O 2 supply (normoxic culture) to mimic stem cell proliferation and commitment. Knockdown of Atg7 expression, a key player in autophagy, in K562 cell line inhibited autophagy compared to control cells. Upon 7 days at 0.1% O 2 both K562 and K562 shATG7 cells stopped to proliferate and a similar amount of viable cells remained. Back to non-restricted O 2 supply K562 cells proliferate whereas K562 shATG7 cells exhibited strong apoptosis. Using immunomagnetic sorted normal and CML CD34 + cells, we inhibited the autophagic process by lentiviral infection expressing shATG7 or using a Vps34 inhibitor. Both, normal and CML CD34 + cells either competent or deficient for autophagy stopped to proliferate in hypoxia. Surprisingly, while normal CD34 + cells proliferate back to non restricted O 2 supply, the CML CD34 + cells deficient for autophagy failed to proliferate. All together, these results suggest that autophagy is required for CML CD34 + commitment while it is dispensable for normal CD34 cells., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to disclose.

Published
2017
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