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1. Transgene-free hematopoietic stem and progenitor cells from human induced pluripotent stem cells

Author

Nathalie Chevallier, Loïc Garçon, Laurence Guyonneau-Harmand, Hélène Lapillonne, Luc Douay, Marc Benderitter, Brigitte Birebent, François Delhommeau, Christophe Desterke, Thierry Jaffredo, Bruno Homme, Alain Chapel, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), EFS Ile de France, Unité d’Ingénierie et de Thérapie Cellulaire, Créteil, F-94017, France., PRP-HOM/SRBE/LRTE, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Unité de service de l'Institut André Lwoff (US 33 Inserm), Hôpital Paul Brousse-Institut André Lwoff [Villejuif] (IAL), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Migration et différenciation des cellules souches hématopoiétiques = Migration and differentiation of hematopoietic stem cells (LBD-E06), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Direction Générale de l’Armement ASTRID/ANR program, Etablissement Français du Sang APR 2013, association 'Combattre La Leucémie', joint grant from Agence Nationale pour la Recherche/California Institute for Regenerative Medicine (ANR/CIRM 0001-02), Laboratoire de Radiopathologie et de Thérapies Expérimentales (IRSN/PRP-HOM/SRBE/LRTE), Unité mixte de service UMS33 [Institut André Lwoff] (UMS33 Inserm/IAL), Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut André Lwoff [Villejuif] (IAL), and Jaffredo, Thierry

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Myeloid, Population, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, CXCR4, 03 medical and health sciences, 0302 clinical medicine, Directed differentiation, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Progenitor cell, education, hemogenic endothelium, 030304 developmental biology, Hemogenic endothelium, 0303 health sciences, education.field_of_study, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Cell biology, hematopoietic stem cells, human induced pluripotent stem cells, Haematopoiesis, hematopoietic reconstitution, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], 030220 oncology & carcinogenesis, Immunology, Homing (hematopoietic)
Abstract

Introductory paragraphThe successful production of Hematopoietic Stem and Progenitor Cells (HSPCs) from human pluripotent sources is conditioned by transgene delivery1-5. We describe here a dedicated and tractable one step, GMP-grade, transgene-free and stroma-free protocol to produce HSPCs from human induced pluripotent stem cells (hiPSCs). This procedure, applied to several sources of hiPSCs with equal efficiency, is based on a directed differentiation with morphogens and cytokines to generate a cell population close to nascent HSPCs or their immediate forerunners i.e., hemogenic endothelial cells6-9. Following engraftment into immunocompromised recipients, this cell population was proved capable of a robust myeloid, lymphoid and definitive red blood cell production in sequential recipients for at least 40 weeks. Further identification of the repopulating cells show that they express the G protein–coupled receptor APELIN (APLNR) and the homing receptor CXCR4. This demonstrates that the generation of bona fide HSPCs from hiPSCs without transgenes is possible and passes through an early endo-hematopoietic intermediate. This work opens the way to the generation of clinical grade HSPCs for the treatment of hematological diseases and holds promise for the analysis of HSPC development in the human species.

Published
2017

2. Molecular signature of erythroblast enucleation in human embryonic stem cells

Author

Nicolas Hebert, Anne-Marie Faussat, Charles Durand, Marie Cambot, Hélène Lapillonne, Shaghayegh Rouzbeh, Christelle Mazurier, Luc Douay, Ladan Kobari, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Transfusion Sanguine [Paris] (INTS), Cancer, Inflammation, Hormones, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Labex GR-Ex fellowship, Etablissement Francais du Sang (EFS), Fondation pour la recherche medicale, Combattre La Leucemie, DIM Stempole (Paris, France), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL-UPMC, Gestionnaire, and Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID

Subjects
Cell type, Embryonic stem cells, Erythroblasts, Enucleation, Human Embryonic Stem Cells, Embryoid body, Biology, MiR-30a, Erythroblast, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Humans, Erythropoiesis, RNA, Messenger, Cells, Cultured, Gene knockdown, Cell Differentiation, Cell Biology, Anatomy, Embryonic stem cell, Cell biology, MicroRNAs, Gene Expression Regulation, Molecular Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Developmental Biology
Abstract

While enucleation is a critical step in the terminal differentiation of human red blood cells, the molecular mechanisms underlying this unique process remain unclear. To investigate erythroblast enucleation, we studied the erythroid differentiation of human embryonic stem cells (hESCs), which provide a unique model for deeper understanding of the development and differentiation of multiple cell types. First, using a two-step protocol, we demonstrated that terminal erythroid differentiation from hESCs is directly dependent on the age of the embryoid bodies. Second, by choosing hESCs in two extreme conditions of erythroid culture, we obtained an original differentiation model which allows one to study the mechanisms underlying the enucleation of erythroid cells by analyzing the gene and miRNA (miR) expression profiles of cells from these two culture conditions. Third, using an integrated analysis of mRNA and miR expression profiles, we identified five miRs potentially involved in erythroblast enucleation. Finally, by selective knockdown of these five miRs we found miR-30a to be a regulator of erythroblast enucleation in hESCs. Stem Cells 2015;33:2431–2441

Published
2015

3. A novel micronucleus in vitro assay utilizing human hematopoietic stem cells

Author

Natalia Kotova, Dag Jenssen, Daniel Vare, Luc Douay, Eva-Lena Härnwall, Christelle Mazurier, Nicolas Hebert, Jan Grawé, Administateur, HAL Sorbonne Université, Stockholm University, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Uppsala University, Service d'immunologie et hématologies biologiques [Saint-Antoine], Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Erythrocytes, Pharmacology and Toxicology, Stem cells, Biology, Toxicology, medicine.disease_cause, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Micronucleus test, medicine, Humans, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Micronucleus Tests, medicine.diagnostic_test, Genotoxicity in vitro, General Medicine, Farmakologi och toxikologi, Hematopoietic Stem Cells, Molecular biology, Coculture Techniques, 3. Good health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Bone marrow, Stem cell, Micronucleus, Genotoxicity, Ex vivo, Mutagens
Abstract

The induction of micronucleated reticulocytes in the bone marrow is a sensitive indicator of chromosomal damage. Therefore, the micronucleus assay in rodents is widely used in genotoxicity and carcinogenicity testing. A test system based on cultured human primary cells could potentially provide better prediction compared to animal tests, increasing patient safety while also implementing the 3Rs principle, i.e. replace, reduce and refine. Hereby, we describe the development of an in vitro micronucleus assay based on animal-free ex vivo culture of human red blood cells from hematopoietic stem cells. To validate the method, five clastogens with direct action, three clastogens requiring metabolic activation, four aneugenic and three non-genotoxic compounds have been tested. Also, different metabolic systems have been applied. Flow cytometry was used for detection and enumeration of micronuclei. Altogether, the results were in agreement with the published data and indicated that a sensitive and cost effective in vitro assay to assess genotoxicity with a potential to high-throughput screening has been developed. (C) 2015 The Authors. Published by Elsevier Ltd.

Published
2015

4. Caspase-3 Is Involved in the Signalling in Erythroid Differentiation by Targeting Late Progenitors

Author

Daniela Boehm, Christelle Mazurier, Dhouha Darghouth, Marie-Catherine Giarratana, Luc Douay, Laurence Harmand, Anne-Marie Faussat, HAL UPMC, Gestionnaire, Différenciation et prolifération des cellules souches adultes. application à la thérapie cellulaire hématopoiétique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Etablissement Français du Sang (EFS), EFS, Cytométrie et Imagerie Saint-Antoine (CISA), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Myeloid, Cell division, Cellular differentiation, Red Cells, lcsh:Medicine, Apoptosis, Biochemistry, 0302 clinical medicine, hemic and lymphatic diseases, Molecular Cell Biology, lcsh:Science, Erythroid Precursor Cells, Cells, Cultured, 0303 health sciences, Multidisciplinary, Caspase 3, Stem Cells, Cell Differentiation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Cell cycle, Caspase Inhibitors, Cell biology, Enzymes, Adult Stem Cells, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Medicine, Cell Division, Signal Transduction, Research Article, G2 Phase, Biology, Cell Growth, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Cell Lineage, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, 030304 developmental biology, Cell Proliferation, Cell growth, lcsh:R, Hematopoietic Stem Cells, Hematopoiesis, Enzyme Activation, lcsh:Q, Developmental Biology
Abstract

International audience; A role for caspase activation in erythroid differentiation has been established, yet its precise mode of action remains elusive. A drawback of all previous investigations on caspase activation in ex vivo erythroid differentiation is the lack of an in vitro model producing full enucleation of erythroid cells. Using a culture system which renders nearly 100% enucleated red cells from human CD34 + cells, we investigated the role of active caspase-3 in erythropoiesis. Profound effects of caspase-3 inhibition were found on erythroid cell growth and differentiation when inhibitors were added to CD34 + cells at the start of the culture and showed dose-response to the concentration of inhibitor employed. Enucleation was only reduced as a function of the reduced maturity of the culture and the increased cell death of mature cells while the majority of cells retained their ability to extrude their nuclei. Cell cycle analysis after caspase-3 inhibition showed caspase-3 to play a critical role in cell proliferation and highlighted a novel function of this protease in erythroid differentiation, i.e. its contribution to cell cycle regulation at the mitotic phase. While the effect of caspase-3 inhibitor treatment on CD34 + derived cells was not specific to the erythroid lineage, showing a similar reduction of cell expansion in myeloid cultures, the mechanism of action in both lineages appeared to be distinct with a strong induction of apoptosis causing the decreased yield of myeloid cells. Using a series of colony-forming assays we were able to pinpoint the stage at which cells were most sensitive to caspase-3 inhibition and found activated caspase-3 to play a signalling role in erythroid differentiation by targeting mature BFU-E and CFU-E but not early BFU-E.

Published
2013

5. Proof of principle for transfusion of in vitro-generated red blood cells

Author

Sabine François, Laurent Kiger, Hélène Lapillonne, Germain Trugnan, Hélène Rouard, Séverine Jolly, Thierry Peyrard, Nicolas Hebert, Nathalie Mario, Tiffany Marie, Laurence Harmand, Christelle Mazurier, Marie-Catherine Giarratana, Luc Douay, Jean-Yves Devaux, Agnès Dumont, Pierre-Yves Le Pennec, Innocent Safeukui, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Thérapie Cellulaire [Grenoble], CHU Grenoble-EFS, Immunologie moléculaire des parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université Pierre et Marie Curie - Paris 6 (UPMC), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Institut National de la Transfusion Sanguine [Paris] (INTS), Centre National de Référence pour les Groupes Sanguins (CNRGS), CNRGS, STMicroelectronics [Crolles] (ST-CROLLES), Service de médecine interne [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Différenciation et prolifération des cellules souches adultes. application à la thérapie cellulaire hématopoiétique, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Erythrocytes, Plenary Paper, Antigens, CD34, Mice, SCID, Biochemistry, Blood cell, Hemoglobins, Mice, 0302 clinical medicine, Mice, Inbred NOD, Erythropoiesis, Cells, Cultured, 0303 health sciences, education.field_of_study, Hematology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Transfusion medicine, Cell Differentiation, Erythrocyte Aging, Flow Cytometry, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Blood Group Antigens, Stem cell, Erythrocyte Transfusion, medicine.medical_specialty, Cell Survival, Immunology, Population, Transplantation, Heterologous, Biology, In Vitro Techniques, 03 medical and health sciences, In vivo, Internal medicine, Erythrocyte Deformability, medicine, Animals, Humans, education, 030304 developmental biology, Cell Proliferation, Severe combined immunodeficiency, Cell Biology, medicine.disease, Hematopoietic Stem Cells, Red blood cell
Abstract

In vitro RBC production from stem cells could represent an alternative to classic transfusion products. Until now the clinical feasibility of this concept has not been demonstrated. We addressed the question of the capacity of cultured RBCs (cRBCs) to survive in humans. By using a culture protocol permitting erythroid differentiation from peripheral CD34+ HSC, we generated a homogeneous population of cRBC functional in terms of their deformability, enzyme content, capacity of their hemoglobin to fix/release oxygen, and expression of blood group antigens. We then demonstrated in the nonobese diabetes/severe combined immunodeficiency mouse that cRBC encountered in vivo the conditions necessary for their complete maturation. These data provided the rationale for injecting into one human a homogeneous sample of 1010 cRBCs generated under good manufacturing practice conditions and labeled with 51Cr. The level of these cells in the circulation 26 days after injection was between 41% and 63%, which compares favorably with the reported half-life of 28 ± 2 days for native RBCs. Their survival in vivo testifies globally to their quality and functionality. These data establish the proof of principle for transfusion of in vitro–generated RBCs and path the way toward new developments in transfusion medicine. This study is registered at http://www.clinicaltrials.gov as NCT0929266.

Published
2011

6. STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma

Author

Christine Perrot, Philippe Gaulard, Paul Coppo, Peggy Dartigues, Hakim Bouamar, Kaiss Lassoued, Yenlin Huang, Félix Agbalika, Sandrine Bouchet, Valérie Gouilleux-Gruart, Luc Douay, Norbert-Claude Gorin, Hicham Bouhlal, Vincent Vieillard, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Différenciation et prolifération des cellules souches adultes. application à la thérapie cellulaire hématopoiétique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïese et cellules souches normales et pathologiques (U790), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement normal et pathologique des lymphocytes et signalisation, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-UF7 EA3963-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), focal, Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de microbiologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, STAT3 Transcription Factor, Cancer Research, [SDV]Life Sciences [q-bio], Nose Neoplasms, bcl-X Protein, Mice, SCID, Lymphoma, T-Cell, Article, Natural killer cell, hemophagocytic syndrome, STAT3, Interferon-gamma, Mice, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, medicine, Animals, Humans, T-cell lymphoma, Cytotoxic T cell, Epstein-Barr virus, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, 030304 developmental biology, 0303 health sciences, Lymphokine-activated killer cell, biology, Cell growth, leukemia, natural killer, Hematology, Janus Kinase 2, Middle Aged, medicine.disease, Natural killer T cell, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female
Abstract

International audience; Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-gamma, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-beta (beta isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.

Published
2009

7. Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome

Author

André Baruchel, Yves Perel, Anne Hagemejier, Guy Leverger, Judith Landman-Parker, Paola Ballerini, Virginie Gandemer, François Sigaux, Gérard Michel, Claudine Schmitt, Vahid Asnafi, Jean Michel Cayuela, Sylvie Fasola, Marie Françoise Auclerc, Luc Douay, Thierry Leblanc, Myriam Labopin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'hématologie, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'onco-hématologie pédiatrique, hôpital Sud, Service d'hématologie pédiatrique et oncologie, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie, Service d'oncologie et hématologie, Hôpital d'enfants, Department of Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), supported by Chugai France (Dr. Thierry Guillot) and SFCE (Société Française des Cancers de l'Enfant)., Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Sud, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Catholic University of Leuven ( KU Leuven ), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), and De Villemeur, Hervé

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Oncology, Time Factors, Transcription, Genetic, MESH : Genotype, MESH : Child, Preschool, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, 0302 clinical medicine, MESH : Child, hemic and lymphatic diseases, MESH: Child, Gene expression, Genotype, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia-Lymphoma, Adult T-Cell, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Medicine, MESH : Female, MESH : Homeodomain Proteins, MESH: Leukemia-Lymphoma, Adult T-Cell, Child, Regulation of gene expression, 0303 health sciences, MESH : Prognosis, Hematology, Hazard ratio, MESH : Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Follow-Up Studies, MESH: Gene Expression Regulation, Neoplastic, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, Prognosis, MESH : Survival Rate, MESH: Infant, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, NUP214-ABL1, Child, Preschool, 030220 oncology & carcinogenesis, outcome, Female, France, TLX3/HOX11L2, MESH : Time Factors, Adult, medicine.medical_specialty, Adolescent, MESH: Survival Rate, MESH : Gene Expression Regulation, Neoplastic, MESH : Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Adolescent, Internal medicine, MESH: Homeodomain Proteins, Humans, MESH : France, Survival rate, 030304 developmental biology, Homeodomain Proteins, MESH: Adolescent, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Transcription, Genetic, MESH : Humans, MESH: Time Factors, MESH: Child, Preschool, Infant, MESH : Transcription, Genetic, childhood T-cell acute lymphoblastic leukemia, MESH : Follow-Up Studies, MESH: Adult, MESH : Leukemia-Lymphoma, Adult T-Cell, MESH: Male, MESH: France, El Niño, Fusion transcript, Immunology, SIL-TAL1, business, MESH: Female, Follow-Up Studies
Abstract

International audience; BACKGROUND: The prognostic value of the ectopic activation of TLX3 gene expression, a major oncogenetic event associated with pediatric T-cell acute lymphoblastic leukemia, is controversial. Likewise, the frequency and the prognostic significance in pediatric T-cell acute lymphoblastic leukemia of the newly characterized NUP214-ABL1 fusion transcript is not yet clear. DESIGN AND METHODS: Two hundred children with T-cell acute lymphoblastic leukemia were treated in the French FRALLE-93 study from 1993 to 1999. The expression of TLX3, TLX1 and SILTAL1 genes was analyzed in samples from 92 patients by real-time quantitative reverse transcriptase polymerase chain reaction. Most of these samples were further studied for NUP214-ABL1 and CALM-AF10 fusion transcripts. RESULTS: The median follow-up was 7.9 years. At 5 years the overall survival (+/- standard deviation, %) was 62 (+/-3%) and leukemia-free survival was 58 (+/-3%). Patients with T-cell acute lymphoblastic leukemia positive for TLX3 had a poorer survival compared to those with T-ALL negative for TLX3 (overall survival: 45+/-11% vs. 57+/-5%, p=0.049). In multivariate analysis, TLX3 expression was an independent adverse risk factor predicting relapse with a hazard ratio of 2.44 (p=0.017) and an overall survival with a hazard ratio of 3.7 (p=0.001). NUP214-ABL1 was expressed in 16.6% of patients with TLX3-positive T-ALL (3 of 18); all of the patients with this association died before completion of the treatment. SILTAL expression did not significantly affect the prognosis of patients with T-cell acute lymphoblastic leukemia. Only three of 92 patients expressed the TLX1 gene and all three are alive. CONCLUSIONS: TLX3 gene expression is an independent risk factor predicting poor survival in childhood T-cell acute lymphoblastic leukemia. When co-expressed with TLX3, NUP214-ABL1 transcripts may increase the risk of poor survival.

Published
2008

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