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9 results on '"MESH : Humans"'

1. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)

Author

Pierre Bordigoni, Danielle Canioni, Michèle Milili, Nathalie Lambert, Claire Galambrun, Marie Ouachée-Chardin, Filomeen Haerynck, Françoise Le Deist, Despina Moshous, Christelle Lenoir, Stephanie Rigaud, Lionel Galicier, Fabien Touzot, Capucine Picard, Mohamed Hamidou, Hirokazu Kanegane, Ester Mejstrikova, Helen Chapel, Eduardo López-Granados, Stéphane Blanche, Alain Dabadie, Jana Pachlopnik Schmid, Pierre-Simon Rohrlich, Fabian Hauck, Geneviève de Saint Basile, Claudin Schiff, Jean-Louis Stephan, Alain Fischer, Isabelle Pellier, Nizar Mahlaoui, Sylvain Latour, Alain Fourmaintraux, Vincent Barlogis, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Graduate School of Medicine, University of Toyama, Department of pediatrics, University of Oxford [Oxford], Teaching Hospital Motol and 2nd Medical School, Charles University, Department of Pediatric Hematology and Oncology, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'immuno-hématologie pédiatrique [CHU Necker], Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Groupe Hospitalier Sud Réunion (GHSR), Centre Hospitalier Universitaire [Rennes], Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Department of Paediatric Pulmonology, Ghent University Hospital, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de pédiatrie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, CHU Saint-Etienne, 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), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'étude des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Service d'Immunologie et d'Hématologie Pédiatrique, Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), University of Oxford, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Collège de France - Chaire Médecine expérimentale (A. Fischer), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-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 Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Groupe Hospitalier Sud Réunion ( GHSR ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)

Subjects
Male, MESH : Retrospective Studies, MESH: X-Linked Inhibitor of Apoptosis Protein, MESH : Aged, MESH : Child, Preschool, Biochemistry, Cohort Studies, Immunoenzyme Techniques, Hypogammaglobulinemia, MESH: Lymphoproliferative Disorders, 0302 clinical medicine, MESH : Child, MESH: Child, hemic and lymphatic diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, XIAP Deficiency, Signaling Lymphocytic Activation Molecule Associated Protein, X-Linked Lymphoproliferative Syndrome, Child, MESH: Cohort Studies, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH : Lymphoproliferative Disorders, Intracellular Signaling Peptides and Proteins, MESH : Infant, Hematology, MESH : Adult, Middle Aged, MESH : Survival Rate, MESH: Infant, 3. Good health, Survival Rate, MESH : Phenotype, Phenotype, MESH: Young Adult, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Survival Rate, MESH : Male, Immunology, MESH : Young Adult, MESH : Cohort Studies, X-Linked Inhibitor of Apoptosis Protein, Biology, MESH: Phenotype, Virus, Young Adult, 03 medical and health sciences, MESH : Intracellular Signaling Peptides and Proteins, MESH : Immunoenzyme Techniques, MESH : Adolescent, MESH: Intracellular Signaling Peptides and Proteins, medicine, Humans, MESH : Middle Aged, MESH: Immunoenzyme Techniques, Aged, Retrospective Studies, 030304 developmental biology, MESH: Adolescent, Hemophagocytic lymphohistiocytosis, Cytopenia, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, X-linked lymphoproliferative disease, MESH: Adult, MESH: Retrospective Studies, Cell Biology, medicine.disease, Lymphoproliferative Disorders, MESH: Male, MESH : X-Linked Inhibitor of Apoptosis Protein, Mutation, Histopathology, MESH: Female, 030215 immunology
Abstract

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.

Published
2011

2. Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia

Author

Franck E. Nicolini, Sandrine Hayette, Ghassan Hamdan, Sandrine Jeanpierre, Francois-Xavier Mahon, Karen Sagorny, Alain Puisieux, Erika Cosset, Thibault Voeltzel, Charles Dumontet, Véronique Maguer-Satta, Laboratoire de Biophotonique et Pharmacologie - UMR 7213 ( LBP ), Centre National de la Recherche Scientifique ( CNRS ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Equipe 11, Centre Léon Bérard [Lyon]-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -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 ), Oncogénèse et progression tumorale, 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 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 de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-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 ), Laboratoire de Biologie Moléculaire, Hospices Civils de Lyon ( HCL ), Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe 14, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), equipe 2, Institut Universitaire de France ( IUF ), Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Université Claude Bernard Lyon 1 (UCBL), Centre Léon Bérard [Lyon]-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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Institut Universitaire de France (IUF), and Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL)

Subjects
MESH : RNA, Messenger, MESH: Piperazines, MESH : Pyrimidines, Antigens, CD34, Drug resistance, MESH : RNA, Small Interfering, Biochemistry, Piperazines, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, hemic and lymphatic diseases, MESH: RNA, Small Interfering, MESH: Protein Kinase Inhibitors, RNA, Small Interfering, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, Nuclear Proteins, MESH: Twist Transcription Factor, Myeloid leukemia, MESH: Gene Expression Regulation, Neoplastic, Hematology, MESH: Drug Resistance, Neoplasm, 3. Good health, Gene Expression Regulation, Neoplastic, Leukemia, MESH : Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Benzamides, Imatinib Mesylate, MESH : Antigens, CD34, Tyrosine kinase, medicine.drug, MESH: Cell Line, Tumor, MESH : Gene Expression Regulation, Neoplastic, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Myelogenous, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, RNA, Messenger, Protein Kinase Inhibitors, MESH: RNA, Messenger, 030304 developmental biology, MESH: Humans, Oncogene, MESH : Cell Line, Tumor, Twist-Related Protein 1, MESH : Twist Transcription Factor, MESH : Humans, MESH : Nuclear Proteins, Imatinib, MESH: Antigens, CD34, Cell Biology, MESH : Protein Kinase Inhibitors, medicine.disease, respiratory tract diseases, Pyrimidines, Imatinib mesylate, MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Drug Resistance, Neoplasm, MESH: Pyrimidines, MESH : Piperazines, Cancer research, MESH : Leukemia, Myelogenous, Chronic, BCR-ABL Positive, MESH: Nuclear Proteins
Abstract

The mechanisms of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) often remain obscure. Analysis of patient samples during disease progression revealed the up-regulation of the oncogene TWIST-1, also measured in primary samples from TKI-resistant patients. Moreover, we found that TWIST-1 was overexpressed in CML diagnostic samples of patients who later developed cytogenetic resistance to imatinib, even those without any detectable resistance mechanism. We confirmed the up-regulation of TWIST-1 at both RNA and protein levels in imatinib-resistant cell lines, irrespective of any other resistance mechanism. Analysis with specific small interfering RNA suggested TWIST-1 involvement in the resistance phenotype. Finally, the kinetics of TWIST-1 expression during the individual medical histories of CML patients indicated that TWIST-1 expression is down-regulated by TKIs and up-regulated with TKI resistance. We hypothesize that the overexpression of the TWIST-1 oncogene represents a novel key prognostic factor potentially useful for optimizing CML management in the TKI era.

Published
2011

3. CD4-CCR5 interaction in intracellular compartments contributes to receptor expression at the cell surface

Author

Georges Bismuth, Mark G.H. Scott, Catherine Labbé-Jullié, Lamia Achour, Hamasseh Shirvani, Stefano Marullo, Alain Thuret, Marullo, Stefano, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Hela Cells, Chemokine receptor CCR5, viruses, Receptor expression, MESH: Antigens, CD4, Intracellular Space, MESH : Intracellular Space, MESH: Cricetinae, Plasma protein binding, MESH: Receptors, CCR5, Endoplasmic Reticulum, Biochemistry, MESH: Cell Compartmentation, MESH : Protein Transport, MESH: Cricetulus, Cell–cell interaction, Cricetinae, MESH : CHO Cells, MESH: Animals, Receptor, Cells, Cultured, MESH : Endoplasmic Reticulum, biology, MESH : Cricetinae, virus diseases, MESH : Protein Binding, MESH : Receptors, CCR5, Hematology, Cell biology, Protein Transport, Antigens, Surface, CD4 Antigens, MESH: Intracellular Space, MESH : Antigens, Surface, Intracellular, MESH: Cells, Cultured, Protein Binding, MESH: Protein Transport, Receptors, CCR5, MESH: Antigens, Surface, MESH : Cricetulus, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CHO Cells, Article, Cricetulus, MESH: CHO Cells, MESH: Endoplasmic Reticulum, MESH : Cells, Cultured, MESH: Protein Binding, Animals, Humans, MESH : Cell Compartmentation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Humans, Endoplasmic reticulum, MESH : Humans, Cell Biology, Cell Compartmentation, MESH: Hela Cells, biology.protein, MESH : Antigens, CD4, MESH : Animals, CC chemokine receptors, HeLa Cells
Abstract

International audience; The association of CD4, a glycoprotein involved in T-cell development and antigen recognition, and CC chemokine receptor 5 (CCR5), a chemotactic G protein-coupled receptor, which regulates trafficking and effector functions of immune cells, forms the main receptor for HIV. We observed that the majority of CCR5 is maintained within the intracellular compartments of primary T lymphocytes and in a monocytic cell line, contrasting with its relatively low density at the cell surface. The CCR5-CD4 association, which occurs in the endoplasmic reticulum, enhanced CCR5 export to the plasma membrane in a concentration-dependent manner, whereas inhibition of endogenous CD4 with small interfering RNAs decreased cell-surface expression of endogenous CCR5. This effect was specific for CCR5, as CD4 did not affect cellular distribution of CXCR4, the other HIV coreceptor. These results reveal a previously unappreciated role of CD4, which contributes to regulating CCR5 export to the plasma membrane.

Published
2009

4. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia

Author

Bernard Mari, Elodie Portales-Casamar, Bruno Cassinat, Evelyne Friederich, Christine Chomienne, Khalil Arar, Pascal Barbry, Thomas Maurin, Anne Saumet, Manuella Bouttier, Laurent Vallar, Guillaume Vetter, Charles-Henri Lecellier, Wyeth W. Wasserman, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cytoskeleton and Cell Plasticity Lab, Université du Luxembourg (Uni.lu), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), University of British Columbia (UBC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Public Santé, CRP-Santé Luxembourg, Sigma-Proligo, Granulopoiese et Processus Leucemiques (UMR_S_718), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université du Luxembourg ( Uni.lu ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), University of British Columbia ( UBC ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Granulopoiese et Processus Leucemiques, and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Oncogene Proteins, Fusion, Transcription, Genetic, Retinoic acid, MESH : Leukemia, Promyelocytic, Acute, MESH : Oncogene Proteins, Fusion, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH : Tumor Markers, Biological, MESH : Homeodomain Proteins, RNA, Neoplasm, MESH : Tretinoin, Regulation of gene expression, 0303 health sciences, Gene Expression Regulation, Leukemic, Myeloid leukemia, Hematology, MESH : Arsenic, 3. Good health, MESH : Antineoplastic Agents, Leukemia, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH: Gene Expression Regulation, Leukemic, medicine.drug, Acute promyelocytic leukemia, MESH: Cell Line, Tumor, Immunology, Antineoplastic Agents, Tretinoin, Biology, MESH : Cell Adhesion Molecules, Arsenic, 03 medical and health sciences, Cell Line, Tumor, MESH: Arsenic, MESH: Homeodomain Proteins, microRNA, Biomarkers, Tumor, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Tretinoin, MESH: Humans, MESH : Cell Line, Tumor, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Cell Biology, MESH: RNA, Neoplasm, medicine.disease, MESH : MicroRNAs, MicroRNAs, MESH : RNA, Neoplasm, MESH : Gene Expression Regulation, Leukemic, chemistry, Retinoic acid receptor alpha, MESH: Tumor Markers, Biological, Cancer research, MESH: Antineoplastic Agents, Cell Adhesion Molecules, MESH: MicroRNAs, MESH: Leukemia, Promyelocytic, Acute, MESH: Oncogene Proteins, Fusion
Abstract

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias.

Published
2009

5. Primary cystic lung light chain deposition disease: a clinicopathologic entity derived from unmutated B cells with a stereotyped IGHV4-34/IGKV1 receptor

Author

Marc Stern, Marie-Hélène Delfau-Larue, Hervé Mal, Diane Damotte, Magali Colombat, Michel Fournier, Patrice Callard, Jacques Diebold, Jean-Pierre Farcet, Christiane Copie-Bergman, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service d'anatomie pathologique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d'immunologie biologique, Service de pneumologie, and Hôpital Foch [Suresnes]

Subjects
Lung Diseases, Pathology, MESH : Molecular Sequence Data, MESH : DNA, medicine.medical_treatment, Immunoglobulin Variable Region, Paraproteinemias, MESH : Immunoglobulin Heavy Chains, Plasma cell, Biochemistry, 0302 clinical medicine, MESH : Female, MESH : Immunoglobulin Variable Region, B-Lymphocytes, 0303 health sciences, MESH : Lung Diseases, Cysts, MESH : Amino Acid Sequence, Hematology, MESH : Adult, MESH : Immunoglobulin Light Chains, 3. Good health, medicine.anatomical_structure, MESH : Paraproteinemias, 030220 oncology & carcinogenesis, MESH : Lung Transplantation, Female, Genes, Immunoglobulin Light Chain, Immunoglobulin Heavy Chains, Lung Transplantation, Adult, medicine.medical_specialty, Genes, Immunoglobulin Heavy Chain, Molecular Sequence Data, Immunology, MESH : Genes, Immunoglobulin Heavy Chain, MESH : Cysts, Biology, Immunoglobulin light chain, Article, Light chain deposition disease, MESH : B-Lymphocytes, Lung Disorder, Immunoglobulin kappa-Chains, 03 medical and health sciences, MESH : Immunoglobulin kappa-Chains, medicine, Humans, Lung transplantation, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Genes, Immunoglobulin Light Chain, 030304 developmental biology, Lung, Base Sequence, MESH : Humans, DNA, Cell Biology, medicine.disease, Immunoglobulin heavy chain, MESH : Base Sequence, Immunoglobulin Light Chains, CD5
Abstract

We have recently described a new form of light chain deposition disease (LCDD) presenting as a severe cystic lung disorder requiring lung transplantation. There was no bone marrow plasma cell proliferation. Because of the absence of disease recurrence after bilateral lung transplantation and of serum-free light chain ratio normalization after the procedure, we hypothesized that monoclonal light chain synthesis occurred within the lung. The aim of this study was to look for the monoclonal B-cell component in 3 patients with cystic lung LCDD. Histologic examination of the explanted lungs showed diffuse nonamyloid κ light chain deposits associated with a mild lymphoid infiltrate composed of aggregates of small CD20+, CD5−, CD10− B lymphocytes reminiscent of bronchus-associated lymphoid tissue. Using polymerase chain reaction (PCR), we identified a dominant B-cell clone in the lung in the 3 studied patients. The clonal expansion of each patient shared an unmutated antigen receptor variable region sequence characterized by the use of IGHV4-34 and IGKV1 subgroups with heavy and light chain CDR3 sequences of more than 80% amino acid identity, a feature evocative of an antigen-driven process. Combined with clinical and biologic data, our results strongly argue for a new antigen-driven primary pulmonary lymphoproliferative disorder.

Published
2008

6. The human spleen is a major reservoir for long-lived vaccinia virus–specific memory B cells

Author

Jean-Claude Weill, Bertrand Godeau, François Paye, Nina Arakelyan, Alain Sauvanet, Pierre Buffet, Odile Beyne-Rauzy, Bruno Varet, Sandra K. Weller, Anne Berger, Jacques-Olivier Pers, Maria Mamani-Matsuda, Claude-Agnès Reynaud, Claire Fieschi, Caroline Staib, Loïc Garçon, Marc Michel, Ahmad Faili, Olivier Hermine, Antonio Cosma, Jean-Marie Andrieu, Développement du Systeme Immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Clinical cooperation group 'Immune monitoring', German Research Center for Environmental Health - Helmholtz Center München (GmbH), Clinical cooperation group 'Antigen-specific immunotherapy', Institute of Molecular Virology, Institute of Virology, Technical University, Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Médecine Interne et Immunopathologie, CHU Toulouse [Toulouse], Laboratoire d'immunologie, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Service d'oncologie médicale [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service de Chirurgie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris], This work was supported by the Fondation Princesse Grace, the Agence Nationale pour la Recherche ('B cell memory', MIIM program) and the Ligue Contre le Cancer (Equipe labellisée). M.M.-M. was supported by successive fellowships from the Fondation de France, the Fondation Singer-Polignac and the Région Ile-de- France, and ANR : 'B cell memory', MIIM program,'B cell memory', MIIM program

Subjects
MESH : Spleen, MESH : Case-Control Studies, MESH : Immunoglobulin G, MESH : Immunologic Memory, Immunology, Naive B cell, Vaccinia virus, Spleen, Biochemistry, Immunoglobulin G, Virus, MESH : B-Lymphocytes, 03 medical and health sciences, 0302 clinical medicine, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Humans, MESH : Splenectomy, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, MESH : Vaccinia virus, biology, MESH : Humans, Cell Biology, Hematology, Virology, 3. Good health, B-1 cell, medicine.anatomical_structure, Case-Control Studies, Splenectomy, biology.protein, Antibody, Million Cells, Immunologic Memory, Homeostasis, 030215 immunology
Abstract

The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special niche. We report that, whereas blood and spleen compartments present similar frequencies of IgG+ cells, antismallpox memory B cells are specifically enriched in the spleen where they account for 0.24% of all IgG+ cells (ie, 10-20 million cells) more than 30 years after vaccination. They represent, in contrast, only 0.07% of circulating IgG+ B cells in blood (ie, 50-100 000 cells). An analysis of patients either splenectomized or rituximab-treated confirmed that the spleen is a major reservoir for long-lived memory B cells. No significant correlation was observed between the abundance of these cells in blood and serum titers of antivaccinia virus antibodies in this study, including in the contrasted cases of B cell– depleting treatments. Altogether, these data provide evidence that in humans, the two arms of B-cell memory—long-lived memory B cells and plasma cells—have specific anatomic distributions—spleen and bone marrow—and homeostatic regulation.

Published
2008

7. HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32)

Author

Virginie Penard-Lacronique, Isabelle André-Schmutz, Xin-Ying Su, Roland Berger, Paola Ballerini, Claudie Lemercier, Véronique Della-Valle, Francine Mugneret, Serge Romana, Michel Lessard, Isabelle Radford-Weiss, Marina Lafage-Pochitaloff, Olivier Bernard, Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Developpement Normal et Pathologique du Système Immunitaire, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, CHU Strasbourg, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des hémopathies humaines (EMI 210), 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 Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Oncogene Proteins, Fusion, Transcription, Genetic, T-Lymphocytes, BCL11B, Chromosomal translocation, MESH : Promoter Regions, Genetic, MESH : Oncogene Proteins, Fusion, Biochemistry, Jurkat cells, Translocation, Genetic, Jurkat Cells, MESH : Chromosomes, Human, Pair 5, 0302 clinical medicine, MESH : Translocation, Genetic, Transcription (biology), MESH: Jurkat Cells, Leukemia-Lymphoma, Adult T-Cell, MESH: Leukemia-Lymphoma, Adult T-Cell, MESH : Homeodomain Proteins, Promoter Regions, Genetic, MESH : Jurkat Cells, Oncogene Proteins, 0303 health sciences, MESH : Chromosomes, Human, Pair 14, MESH : Oncogene Proteins, MESH : Tumor Suppressor Proteins, Cell Differentiation, Hematology, Transfection, MESH: Translocation, Genetic, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, MESH : DNA-Binding Proteins, MESH : Repressor Proteins, MESH : Cell Differentiation, MESH: Cell Differentiation, MESH: Chromosomes, Human, Pair 5, T cell, Immunology, Biology, 03 medical and health sciences, MESH: Oncogene Proteins, MESH: Promoter Regions, Genetic, MESH: Homeodomain Proteins, medicine, Humans, MESH: Tumor Suppressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Chromosomes, Human, Pair 14, Homeodomain Proteins, MESH : T-Lymphocytes, MESH: Humans, Recombinase activity, Tumor Suppressor Proteins, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Cell Biology, T lymphocyte, Molecular biology, MESH : Leukemia-Lymphoma, Adult T-Cell, Repressor Proteins, MESH: T-Lymphocytes, MESH: Chromosomes, Human, Pair 14, MESH: DNA-Binding Proteins, MESH: Oncogene Proteins, Fusion
Abstract

International audience; The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.

Published
2006

8. Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Author

Jean-Christophe Thalabard, Agnès Rötig, Z. Ioav Cabantchik, Serge Gallet, Anne Leroy-Willig, Arnold Munnich, Kim Hanh Le Quan Sang, Daniel Sidi, Francis Brunelle, Nathalie Boddaert, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Hôpital de Montluçon, Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de cardiologie pédiatrique [CHU Necker], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Pathology, Cardiomyopathy, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH : Brain Chemistry, MESH : Pyridones, Biochemistry, MESH : Iron, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Degenerative disease, MESH : Female, Deferiprone, MESH: Brain Chemistry, MESH: Treatment Outcome, chemistry.chemical_classification, 0303 health sciences, MESH: Iron, [STAT.AP]Statistics [stat]/Applications [stat.AP], Hematology, Brain, MESH : Adult, MESH: Friedreich Ataxia, MESH: Case-Control Studies, Magnetic Resonance Imaging, 3. Good health, Treatment Outcome, Female, MESH : Iron Chelating Agents, medicine.symptom, Adult, medicine.medical_specialty, MESH : Case-Control Studies, Ataxia, Adolescent, Pyridones, MESH : Male, MESH: Biological Transport, Iron, Immunology, Inflammation, MESH : Treatment Outcome, Iron Chelating Agents, Central nervous system disease, 03 medical and health sciences, MESH: Brain, Internal medicine, MESH : Adolescent, MESH : Magnetic Resonance Imaging, MESH: Pyridones, medicine, Humans, 030304 developmental biology, MESH: Adolescent, Brain Chemistry, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, business.industry, MESH : Humans, [ STAT.AP ] Statistics [stat]/Applications [stat.AP], MESH: Adult, Biological Transport, Cell Biology, medicine.disease, MESH: Male, MESH : Biological Transport, Endocrinology, chemistry, MESH : Brain, Transferrin, MESH: Iron Chelating Agents, Friedreich Ataxia, Case-Control Studies, MESH : Friedreich Ataxia, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membrane-permeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with age-matched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s(-1) (+/- 1.6 s(-1)) to 15.7 s(-1) (+/- 0.7 s(-1); P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r = 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neuropathy and ataxic gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and hematologic disorders.

Published
2007

9. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study

Author

Lucienne Chatenoud, Loïc Bergougnoux, Augustin Ferrant, Franck Morschhauser, Gérard Socié, Raoul Herbrecht, Peter Vandenberghe, Samira Fafi-Kremer, Noel Milpied, Gilles Salles, Arnaud Jaccard, Véronique Leblond, Alain Fischer, Philippe Lang, Anne Moreau, Walter Feremans, Sylvain Choquet, Patrice Morand, Olivier Hermine, Eric Oksenhendler, Thierry Lamy, Fritz Offner, Etienne Vilmer, Anne-Marie Stoppa, Yvon Lebranchu, Nathalie Berriot-Varoqueaux, Marie-Noëlle Peraldi, Jeanne Luce Garnier, Unité d'hématologie et de transplantation, Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Immunologie et d'Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP), Biophysique, Médecine Nucléaire et Technologies Médicales ( EA 1049 ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Département de pathologie, Hospices Civils de Lyon ( HCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Registre National des Hémopathies malignes de l'Enfant ( RNHE ), Institut de Veille Sanitaire (INVS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de néphrologie et transplantation, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de néphrologie et immunologie clinique, Hôpital Bretonneau-Université de Tours-CHRU Tours, Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations ( PMRIL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Interaction virus-hôte et maladies du foie, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Virologie moléculaire et structurale, CHU Grenoble, Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biophysique, Médecine Nucléaire et Technologies Médicales (EA 1049), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Registre National des Hémopathies malignes de l'Enfant (RNHE), Institut de Veille Sanitaire (INVS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de virologie moléculaire et structurale (LVMS), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), and Université de Tours (UT)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau

Subjects
Male, MESH: Remission Induction, medicine.medical_treatment, MESH : Prospective Studies, MESH : Aged, Phases of clinical research, Biochemistry, Gastroenterology, Organ transplantation, MESH: Antibodies, Monoclonal, MESH : Organ Transplantation, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, MESH: Lymphoproliferative Disorders, hemic and lymphatic diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, Prospective Studies, Prospective cohort study, MESH: Aged, B-Lymphocytes, MESH: Middle Aged, MESH : Lymphoproliferative Disorders, MESH: Hydro-Lyases, Remission Induction, Antibodies, Monoclonal, Immunosuppression, Hematology, MESH : Adult, Middle Aged, 3. Good health, MESH : Antineoplastic Agents, surgical procedures, operative, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Disease-Free Survival, Rituximab, Female, medicine.drug, Adult, medicine.medical_specialty, Adolescent, MESH : Male, Immunology, Lymphoproliferative disorders, MESH: Organ Transplantation, MESH : Hydro-Lyases, Antineoplastic Agents, Disease-Free Survival, MESH : B-Lymphocytes, 03 medical and health sciences, Internal medicine, MESH: B-Lymphocytes, MESH : Adolescent, medicine, Humans, MESH : Middle Aged, Hydro-Lyases, Aged, MESH: Adolescent, MESH : Remission Induction, MESH: Humans, business.industry, MESH : Humans, MESH: Adult, Cell Biology, Organ Transplantation, medicine.disease, MESH: Male, MESH: Prospective Studies, Lymphoproliferative Disorders, Surgery, Transplantation, Clinical trial, MESH: Disease-Free Survival, MESH: Antineoplastic Agents, business, MESH: Female, 030215 immunology
Abstract

International audience; B-cell posttransplantation lymphoproliferative disorder (B-PTLD) is a rare but severe complication of transplantation, with no consensus on best treatment practice. This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Forty-six patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%. We conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.

Published
2005

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