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27 results on '"MESH: Translocation, Genetic"'

1. Chromosomal abnormalities in 163 Tunisian couples with recurrent miscarriages

Author

Islem Messaoudi, Zouhour Belghith, Nabila Abidli, Imen Chemkhi, Wajih Hammami, Helmy Guermani, Wiem Ayed, Rim Obay, Ahlem Amouri, Département d'Histologie et de Cytogénétique - Institut Pasteur de Tunis, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté de Médecine de Tunis, Université de Tunis El Manar (UTM), Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), and Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis

Subjects
Male, [SDV]Life Sciences [q-bio], Aneuploidy, Chromosome Disorders, Chromosomal translocation, medicine.disease_cause, Translocation, Genetic, Cohort Studies, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, Recurrent miscarriage, Prevalence, Case Series, MESH: Cohort Studies, MESH: Chromosome Disorders, 030219 obstetrics & reproductive medicine, MESH: Abortion, Habitual, Karyotype, General Medicine, MESH: Translocation, Genetic, 3. Good health, Cytogenetic Analysis, Female, 030211 gastroenterology & hepatology, Recurrent miscarriage, chromosomal abnormalities, karyotype, MESH: Tunisia, Adult, Abortion, Habitual, medicine.medical_specialty, Tunisia, Robertsonian translocation, 03 medical and health sciences, medicine, Humans, MESH: Chromosome Aberrations, MESH: Prevalence, Chromosome Aberrations, Gynecology, MESH: Humans, business.industry, MESH: Cytogenetic Analysis, Chromosome, MESH: Adult, medicine.disease, MESH: Male, karyotype, chromosomal abnormalities, MESH: Karyotyping, Karyotyping, Etiology, business, MESH: Female
Abstract

International audience; Recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses before 24 weeks of gestation. Parental chromosomal abnormalities represent an important etiology of RM. The aim of the present study was to identify the distribution of chromosome abnormalities among Tunisian couples with RM referred to the Department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia) during the last five years. Standard cytogenetic analysis was carried out in a total of 163 couples presenting with two or more spontaneous abortions. Karyotypes were analyzed by R-banding. We identified 14 chromosomal abnormalities including autosomal reciprocal translocation, Robertsonian translocation, inversion, mosaic aneuploidy and heteromorphysm. The overall prevalence of chromosomal abnormalities was 8.5% in our cohort. This finding underlies the importance of cytogenetic investigations in the routine management of RM.

Published
2017
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2. RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'

Author

Vered Gigi, Martina Mijušković, Wenzhao Meng, David Roth, Eline T. Luning Prak, Ludovic Deriano, Susanna M. Lewis, Olga Shestova, University of Pennsylvania [Philadelphia], Développement lymphocytaire et Oncogénèse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [CA-104588 to D.B.R., 1R21AI097825-01 to S.M.L.]., University of Pennsylvania, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
p53, DNA End-Joining Repair, Lymphoma, MESH: V(D)J Recombination, Mutant, MESH: DNA Breaks, Double-Stranded, MESH: Genes, p53, Genome Integrity, Repair and Replication, MESH: Mice, Knockout, Translocation, Genetic, chemistry.chemical_compound, Double-Stranded, Mice, 0302 clinical medicine, Receptors, Recombinase, DNA Breaks, Double-Stranded, MESH: Animals, MESH: Ku Autoantigen, DNA Breaks, Sequence Deletion, Mice, Knockout, Genetics, 0303 health sciences, DNA-Binding Proteins/*genetics, V(D)J recombination, Antigens, Nuclear, MESH: Receptors, Antigen, T-Cell, Nuclear/genetics, MESH: Sequence Deletion, MESH: Translocation, Genetic, DNA-Binding Proteins, 030220 oncology & carcinogenesis, Antigen, embryonic structures, [SDV.IMM]Life Sciences [q-bio]/Immunology, Knockout, Receptors, Antigen, T-Cell, Lymphoma/genetics, Translocation, Biology, DNA-binding protein, DNA sequencing, 03 medical and health sciences, Genetic, Animals, Antigens, Gene, Ku Autoantigen, MESH: Antigens, Nuclear, MESH: Mice, 030304 developmental biology, fungi, MESH: DNA End-Joining Repair, Genes, p53, V(D)J Recombination, enzymes and coenzymes (carbohydrates), chemistry, Genes, T-Cell/genetics, MESH: Lymphoma, DNA, MESH: DNA-Binding Proteins
Abstract

International audience; DNA double-stranded breaks (DSBs) can be repaired by several mechanisms, including classical NHEJ (c-NHEJ) and a poorly defined, error-prone process termed alternative NHEJ (a-NHEJ). How cells choose between these alternatives to join physiologic DSBs remains unknown. Here, we show that deletion of RAG2's C-terminus allows a-NHEJ to repair RAG-mediated DSBs in developing lymphocytes from both c-NHEJ-proficient and c-NHEJ-deficient mice, demonstrating that the V(D)J recombinase influences repair pathway choice in vivo. Analysis of V(D)J junctions revealed that, contrary to expectation, junctional characteristics alone do not reliably distinguish between a-NHEJ and c-NHEJ. These data suggest that a-NHEJ is not necessarily mutagenic, and may be more prevalent than previously appreciated. Whole genome sequencing of a lymphoma arising in a p53(-/-) mouse bearing a C-terminal RAG2 truncation reveals evidence of a-NHEJ and also of aberrant recognition of DNA sequences resembling RAG recognition sites.

Published
2014
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3. Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma

Author

Dirk Hose, Jérôme Moreaux, Alexei Protopopov, Anna Jauch, Franck Pellestor, Bernard Klein, Thierry Rème, Hartmut Goldschmidt, Gareth J. Morgan, Brian A Walker, Alboukadel Kassambara, Véronique Pantesco, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Section of Haemato-Oncology, Royal Cancer Hospital-Institute of Cancer Research (ICR), Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute [Boston]-Department of Medical Oncology, Ligue Nationale Contre le Cancer (LNCC, équipe labellisée), Paris, France, The Hopp Foundation, Germany, the University of Heidelberg, Germany, The National Centre for Tumor Diseases, Heidelberg/Mannheim, Germany, European Project, Frei, Monique, FP7 OverMyr - INCOMING, and Universität Heidelberg [Heidelberg] = Heidelberg University

Subjects
spike (sub)bands, DNA Copy Number Variations, [SDV.IMM] Life Sciences [q-bio]/Immunology, Gene regulatory network, Chromosomal translocation, MESH: Multiple Myeloma, Biology, survival, Translocation, Genetic, MESH: Prognosis, 03 medical and health sciences, MESH: Gene Expression Profiling, 0302 clinical medicine, medicine, Cluster Analysis, Humans, molecular biology, Gene Regulatory Networks, Gene, Multiple myeloma, 030304 developmental biology, MESH: Gene Regulatory Networks, Genetics, 0303 health sciences, Expressed sequence tag, MESH: Humans, Gene Expression Profiling, Chromosome, Hematology, MESH: Gene Expression Regulation, Neoplastic, medicine.disease, MESH: Cluster Analysis, MESH: Translocation, Genetic, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, myeloma, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Spike (software development), MESH: DNA Copy Number Variations, prognosis, Original Articles and Brief Reports, Multiple Myeloma
Abstract

International audience; BACKGROUND: Genetic abnormalities are common in patients with multiple myeloma, and may deregulate gene products involved in tumor survival, proliferation, metabolism and drug resistance. In particular, translocations may result in a high expression of targeted genes (termed spike expression) in tumor cells. We identified spike genes in multiple myeloma cells of patients with newly-diagnosed myeloma and investigated their prognostic value. DESIGN AND METHODS: Genes with a spike expression in multiple myeloma cells were picked up using box plot probe set signal distribution and two selection filters. RESULTS: In a cohort of 206 newly diagnosed patients with multiple myeloma, 2587 genes/expressed sequence tags with a spike expression were identified. Some spike genes were associated with some transcription factors such as MAF or MMSET and with known recurrent translocations as expected. Spike genes were not associated with increased DNA copy number and for a majority of them, involved unknown mechanisms. Of spiked genes, 36.7% clustered significantly in 149 out of 862 documented chromosome (sub)bands, of which 53 had prognostic value (35 bad, 18 good). Their prognostic value was summarized with a spike band score that delineated 23.8% of patients with a poor median overall survival (27.4 months versus not reached, P

Published
2012
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4. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters

Author

Joaquin Zacarias-Cabeza, Romain Fenouil, Marta Gut, Albane Lamy de la Chapelle, Martin Heidemann, Corinna Hintermair, Thomas K Albert, Dirk Eick, Jean-Christophe Andrau, Frederic Koch, Salvatore Spicuglia, Pierre Cauchy, Pierre Ferrier, Ivo Gut, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Otto-von-Guericke University [Magdeburg] (OVGU), Helmholtz-Zentrum München (HZM), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), and Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
Polyadenylation, RNA polymerase II, Enhancer RNAs, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Structural Biology, RNA polymerase, MESH: Gene Library, Animals, Promoter Regions, Genetic, Enhancer, Molecular Biology, MESH: Neurofibromatosis 1, 030304 developmental biology, Genetics, 0303 health sciences, MESH: Humans, biology, General transcription factor, Promoter, DNA, MESH: Translocation, Genetic, 3. Good health, Cell biology, MESH: Cell Line, Enhancer Elements, Genetic, chemistry, MESH: DNA Transposable Elements, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, CpG Islands, RNA Polymerase II, Transcription Factors, General, Transcription Initiation Site, Transcription factor II D, MESH: Chromosome Mapping, MESH: Chromosomes, Human, Pair 17, 030217 neurology & neurosurgery
Abstract

International audience; Recent work has shown that RNA polymerase (Pol) II can be recruited to and transcribe distal regulatory regions. Here we analyzed transcription initiation and elongation through genome-wide localization of Pol II, general transcription factors (GTFs) and active chromatin in developing T cells. We show that Pol II and GTFs are recruited to known T cell-specific enhancers. We extend this observation to many new putative enhancers, a majority of which can be transcribed with or without polyadenylation. Importantly, we also identify genomic features called transcriptional initiation platforms (TIPs) that are characterized by large areas of Pol II and GTF recruitment at promoters, intergenic and intragenic regions. TIPs show variable widths (0.4-10 kb) and correlate with high CpG content and increased tissue specificity at promoters. Finally, we also report differential recruitment of TFIID and other GTFs at promoters and enhancers. Overall, we propose that TIPs represent important new regulatory hallmarks of the genome.

Published
2011
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5. Early steps of follicular lymphoma pathogenesis

Author

Roulland, Sandrine, Faroudi, Mustapha, Mamessier, Emilie, Sungalee, Stéphanie, Salles, Gilles, Nadel, Bertrand, 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), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
MESH: Genes, bcl-2, Lymphoma, bcl-2, Translocation, Receptors, Fc, Lymphocyte Activation, Translocation, Genetic, Mice, MESH: Lymphoma, Follicular, Genetic, MESH: B-Lymphocytes, Receptors, Animals, Humans, MESH: Animals, MESH: Lymphocyte Activation, Lymphoma, Follicular, MESH: Mice, B-Lymphocytes, MESH: Humans, Fc, Follicular, MESH: Translocation, Genetic, Genes, bcl-2, DNA-Binding Proteins, Genes, Proto-Oncogene Proteins c-bcl-2, MESH: Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-bcl-6, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Receptors, Fc, MESH: DNA-Binding Proteins
Abstract

International audience; Follicular lymphoma (FL) pathogenesis is a complex and fascinating multi-hit process, escalating along successive derailments of the distinctive molecular and cellular mechanisms paving B-cell differentiation and activation. This progressive subversion of B-cell receptor diversification mechanisms and B-cell homeostasis likely occurs during a protracted preclinical phase of asymptomatic growth, in which premalignant clones already disseminate and establish "niches" in secondary lymphoid organs. Following FL diagnosis, a parallel indolent behavior is observed in most patients, slowly progressing over a period of many years, to eventually generate a highly refractory (and in some case transform into an aggressive subtype of) lymphoma. Novel insights in human germinal center B-cell biology recently allowed a more comprehensive understanding of the various illegitimate events sequentially involved in the premalignant progression phases. In this review, we will discuss how these new data have modified our perception of early FL pathogenesis, the new questions and challenges it opened up, and how this knowledge could impact on innovative programs of early detection, follow-up, and patient management.

Published
2011
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6. 1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma

Author

Stéphanie Chauvelier, Alexandra Debernardi, Katia Delaval, Robert Feil, Remy Gressin, Alexandra Fournier, Martin Figeac, Alicia Lajmanovich, Aurélie Granjon, Christine Lefebvre, Mary Callanan, Yves Usson, Claire Vourc'h, Kassambara Alboukadel, Sophie Rousseaux, John De Vos, Alexei Grichine, Juliana Bruder Ribeyron, Florence de Fraipont, Jean-Pierre Kerckaert, Leila Barki, Thierry Bonnefoix, Anne McLeer-Florin, Saadi Khochbin, Sieme Hamaidia, Samuel Duley, Dominique Leroux, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité de Cancérologie Biologique et biothérapies, Génomique (Plate-Forme) - Genomics Platform, Institut Pasteur [Paris] (IP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), INSERM U823, équipe 10 (Stress et Dynamique de l'Organisation du Génome), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Funding was from the Fondation de France, the Institut National du Cancer (EpiPro network, the programme 'Developpement de plateformes hospitalières de génétique moléculaire des cancers', the P.A.I.R 'Mantle Cell Lymphoma network' and the INCa-DHOS translational research programme 'CT-Lymph'). Additional funding was obtained from the Région Rhone-Alpes programme 'Thématique prioritaire--Cancer', the canceropôle CLARA (EpiMed), the Ligue Nationale Contre le Cancer (LNCC)--Comités de l'Isère/Savoie, the Délegation Régionale de la Recherche Clinique--CHU de Grenoble, the French GOELAMS clinical trials group and the ARAMIS association. AD and JBR have been recruited through the INCa-DHOS 'CT-Lymph' program. AF has been the recipient of doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche, the Association pour la Recherche sur le Cancer (ARC) and the Société Française d'Hématologie (SFH), AMLF of post-doctoral funding from the ARC-ARECA network 'epigenetic profiling in breast and haematological tumours', LB of doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche and the LNCC, MC of a Contrat d'Interface INSERM/Grenoble University Hospital Centre (2006-2011). Affymetrix microarrays were processed in the Microarray Core Facility of the Institute of Research on Biotherapy, CHRU-INSERM-UM1 Montpellier, http://irb.chu-montpellier.fr, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Unité de Cancérologie Biologique et biothérapies, Génomique (Plate-Forme), Institut Pasteur [Paris], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Département de cancérologie et d'hématologie, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Duley, Samuel

Subjects
Genome instability, Chromosomal translocation, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Chromosomes, Human, Pair 2, MESH : Chromosomes, Human, Pair 1, Translocation, Genetic, 0302 clinical medicine, MESH : Lymphoma, B-Cell, MESH : Translocation, Genetic, Heterochromatin, B-cell lymphoma, 0303 health sciences, MESH : Cell Nucleus, GMCL1, MESH: Gene Expression Regulation, Neoplastic, MESH: Translocation, Genetic, Gene Expression Regulation, Neoplastic, MESH: Heterochromatin, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, heterochromatic foci, Molecular Medicine, MESH: Cell Nucleus, Lymphoma, B-Cell, MESH : Gene Expression Regulation, Neoplastic, MESH: Chromosomes, Human, Pair 1, MESH: Chromosomes, Human, Pair 2, Biology, 1q12 pericentric heterochromatin, 03 medical and health sciences, medicine, Constitutive heterochromatin, Humans, Epigenetics, 030304 developmental biology, MESH: Lymphoma, B-Cell, Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Heterochromatin, MESH : Humans, medicine.disease, B cell lymphoma, nuclear architecture, Cancer research, Heterochromatin protein 1, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Diffuse large B-cell lymphoma, Reports
Abstract

International audience; Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours--those targeting 1q12 satellite DNA--can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range 'pairing' between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.

Published
2010
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7. Fusion of EWSR1 with the DUX4 facioscapulohumeral muscular dystrophy region resulting from t(4;22)(q35;q12) in a case of embryonal rhabdomyosarcoma

Author

Nathalie Ebran, Rita Attias, Nicolas Sirvent, Martine Trassard, Florence Pedeutour, Laboratory of Solid Tumors Genetics, Nice University Hospital, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Cancer Research, Pathology, Oncogene Proteins, Fusion, Chromosomes, Human, Pair 22, Chromosomal translocation, Translocation, Genetic, 0302 clinical medicine, Facioscapulohumeral muscular dystrophy, Rhabdomyosarcoma, Embryonal, MESH: In Situ Hybridization, Fluorescence, Muscular dystrophy, MESH: Chromosomes, Human, Pair 22, Rhabdomyosarcoma, [SDV.BDD]Life Sciences [q-bio]/Development Biology, In Situ Hybridization, Fluorescence, MESH: Rhabdomyosarcoma, Embryonal, Genetics, 0303 health sciences, medicine.diagnostic_test, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Immunohistochemistry, Muscular Dystrophy, Facioscapulohumeral, MESH: Translocation, Genetic, MESH: Young Adult, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Female, Chromosomes, Human, Pair 4, Adult, medicine.medical_specialty, MESH: Chromosomes, Human, Pair 4, MESH: Muscular Dystrophy, Facioscapulohumeral, In situ hybridization, MESH: Microscopy, Electron, Biology, 03 medical and health sciences, Young Adult, DUX4, MESH: Homeodomain Proteins, medicine, Humans, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Humans, MESH: Cytogenetic Analysis, MESH: Adult, MESH: Immunohistochemistry, medicine.disease, Microscopy, Electron, MESH: RNA-Binding Proteins, MESH: Calmodulin-Binding Proteins, Calmodulin-Binding Proteins, Embryonal rhabdomyosarcoma, RNA-Binding Protein EWS, MESH: Nuclear Proteins, MESH: Female, Fluorescence in situ hybridization, MESH: Oncogene Proteins, Fusion
Abstract

International audience; Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and rarely occurs in adults. There are six main subtypes, each histologically, clinically, and cytogenetically distinct. Embryonal RMS is characterized by chromosomal gains, usually not associated with any consistent structural anomaly. We describe here a case of embryonal RMS in a 19-year-old female patient. The conventional cytogenetic analysis showed a t(4;22)(q35;q12) translocation as the sole cytogenetic change. Complementary fluorescence in situ hybridization analysis showed that the translocation breakpoints were located in the EWSR1 gene at 22q12 and the region of the DUX4 and FSHMD1A at 4q35. This constitutes a novel example of the high frequency of EWSR1 rearrangements in various types of sarcomas as well as of its ability to fuse with a large variety of partner genes. Because DUX4 is involved in myogenic differentiation and cell-cycle control, the striated muscle differentiation observed in the present case might be a direct consequence of the alteration of the DUX4 region generated by the t(4;22). The involvement of the DUX4 region might represent the genetic hallmark of a novel subclass of small round cell tumors.

Published
2009
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8. Agricultural pesticide exposure and the molecular connection to lymphomagenesis

Author

Pierre Grenot, Yannick Lecluse, Pierre Lebailly, Pascal Gauduchon, Sandrine Roulland, Julie Agopian, Bertrand Nadel, Philippe Ruminy, Mélanie Briand, Jean-Marc Navarro, Anne-claire Gac, 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), Groupe Régional d'Etudes sur le CANcer (GRECAN), IFR146-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146

Subjects
Male, Cytidine deaminase activity, Follicular lymphoma, Chromosomal translocation, MESH: Base Sequence, Somatic evolution in cancer, Translocation, Genetic, MESH: Occupational Exposure, MESH: Genotype, MESH: Lymphoma, Follicular, 0302 clinical medicine, Genotype, Immunology and Allergy, Lymphoma, Follicular, 0303 health sciences, MESH: Middle Aged, MESH: Genetic Predisposition to Disease, Cytidine deaminase, Middle Aged, Phenotype, MESH: Translocation, Genetic, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: B-Lymphocyte Subsets, Adult, Molecular Sequence Data, Immunology, B-Lymphocyte Subsets, Biology, MESH: Phenotype, 03 medical and health sciences, Occupational Exposure, medicine, Humans, Genetic Predisposition to Disease, MESH: Agricultural Workers' Diseases, MESH: Pesticides, Pesticides, 030304 developmental biology, Chromosomes, Human, Pair 14, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, Brief Definitive Report, MESH: Adult, medicine.disease, MESH: Male, Agricultural Workers' Diseases, Lymphoma, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, MESH: Chromosomes, Human, Pair 18
Abstract

International audience; The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18)(+) non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18)(+) B cells. We further demonstrate that such t(14;18)(+) clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18)(+) clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression.

Published
2009
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9. t(11;14)-positive clones can persist over a long period of time in the peripheral blood of healthy individuals

Author

Pierre Lebailly, Sandrine Roulland, Gac Ac, Yannick Lecluse, Pascal Gauduchon, Bertrand Nadel, Groupe Régional d'Etudes sur le CANcer ( GRECAN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ) -IFR146, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), 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 ), Groupe Régional d'Etudes sur le CANcer (GRECAN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cancer Research, Translocation, Genetic, 0302 clinical medicine, MESH : Translocation, Genetic, Long period, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Middle Aged, MESH : Chromosomes, Human, Pair 14, MESH : Chromosomes, Human, Pair 11, food and beverages, Hematology, Middle Aged, MESH : Adult, MESH: Translocation, Genetic, 3. Good health, Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Healthy individuals, [SDV.IMM]Life Sciences [q-bio]/Immunology, Adult, MESH : Male, Biology, 03 medical and health sciences, mental disorders, Humans, MESH : Middle Aged, 030304 developmental biology, Chromosomes, Human, Pair 14, Blood Cells, MESH: Humans, Chromosomes, Human, Pair 11, MESH: Blood Cells, fungi, MESH: Clone Cells, MESH : Humans, MESH : Clone Cells, MESH: Adult, MESH : Cell Transformation, Neoplastic, Peripheral blood, MESH: Male, Clone Cells, MESH: Cell Transformation, Neoplastic, Immunology, MESH : Blood Cells, MESH: Chromosomes, Human, Pair 14, MESH: Chromosomes, Human, Pair 11
Abstract

t(11;14)-positive clones can persist over a long period of time in the peripheral blood of healthy individuals

Published
2009
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10. Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas

Author

Philippe Gaulard, Marie-Hélène Delfau-Larue, Andreas Chott, Christiane Copie-Bergman, Berthold Streubel, Teresa Marafioti, Giovanna Roncador, Steven Le Gouill, Barbara Petit, Corinne Haioun, Bettina Fabiani, Nadine Martin-Garcia, Yenlin Huang, Fanny Gaillard, Jehan Dupuis, Marwan Qubaja, Anne Moreau, 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), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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'hématologie clinique, Departement of Pathology, Medizinische Universität Wien = Medical University of Vienna, Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Service d'anatomie et cytologie pathologiques [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), Monoclonal antibodies unit, Centro Nacional de Investigaciones Oncológicas, Service d'immunologie biologique, Leukaemia Research Immunodiagnostics Unit, University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital], Guellaen, Georges, and University of Oxford- John Radcliffe Hospital [Oxford University Hospital]

Subjects
Antigens, Differentiation, T-Lymphocyte, Pathology, Biopsy, Programmed Cell Death 1 Receptor, MESH: Antigens, CD4, Translocation, Genetic, MESH: Immunoblastic Lymphadenopathy, MESH: Genotype, MESH: Lymphoma, Follicular, MESH: Biopsy, 0302 clinical medicine, Immunophenotyping, MESH: Aged, 80 and over, follicular helper T cell, hemic and lymphatic diseases, MESH: In Situ Hybridization, Fluorescence, Lymphoma, Follicular, peripheral T-cell lymphoma, MESH: Antigens, CD, In Situ Hybridization, Fluorescence, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Neprilysin, T-Lymphocytes, Helper-Inducer, MESH: Gene Expression Regulation, Neoplastic, MESH: Neoplasm Staging, Middle Aged, MESH: Lymphoma, T-Cell, Peripheral, MESH: Gene Rearrangement, T-Lymphocyte, MESH: Translocation, Genetic, 3. Good health, DNA-Binding Proteins, Europe, Gene Expression Regulation, Neoplastic, Phenotype, medicine.anatomical_structure, B symptoms, 030220 oncology & carcinogenesis, CD4 Antigens, Proto-Oncogene Proteins c-bcl-6, Chromosomes, Human, Pair 5, Neprilysin, MESH: Chemokine CXCL13, Anatomy, medicine.symptom, Chromosomes, Human, Pair 9, Adult, MESH: Chromosomes, Human, Pair 5, medicine.medical_specialty, Angioimmunoblastic T-cell lymphoma, Genotype, MESH: Immunophenotyping, T cell, Biology, Gene Rearrangement, T-Lymphocyte, MESH: Phenotype, Follicular cell, Article, Pathology and Forensic Medicine, angioimmunoblastic T-cell lymphoma, Inducible T-Cell Co-Stimulator Protein, 03 medical and health sciences, Antigens, CD, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: T-Lymphocytes, Helper-Inducer, Aged, Neoplasm Staging, 030304 developmental biology, MESH: Humans, MESH: Apoptosis Regulatory Proteins, Lymphoma, T-Cell, Peripheral, MESH: Adult, Gene rearrangement, medicine.disease, Chemokine CXCL13, Peripheral T-cell lymphoma, Lymphoma, MESH: Antigens, Differentiation, T-Lymphocyte, Immunoblastic Lymphadenopathy, Surgery, MESH: Europe, Apoptosis Regulatory Proteins, MESH: Chromosomes, Human, Pair 9, MESH: DNA-Binding Proteins
Abstract

International audience; Rare cases of peripheral T-cell lymphomas with follicular growth pattern (PTCL-F) have been recently reported, and their association with t(5;9)(q33;q22) involving ITK and SYK has been suggested. However, the clinicopathologic aspects of PTCL-F are poorly described and the normal cell counterpart of this subgroup of lymphoma is still unknown. Therefore, we analyzed the pathologic, phenotypic, and cytogenetic features of a series of 30 patients (range: 33 to 88 y) that showed histopathologic features of PTCL-F in at least 1 biopsy (n=30), either at initial presentation (n=26) or at relapse (n=4). Neoplastic cells were medium-sized clear cells that were CD4+ (24/27, 89%), CD10+ (21/29, 72%), BCL-6+ (14/19, 74%), and expressed programed death-1 (27/27, 100%), CXCL13 (23/27, 85%), and ICOS (11/11, 100%), markers of follicular helper T cells (TFH). Four of 22 patients (18%) had t(5;9)(q33;q22) detected by fluorescence in situ hybridization. Patients with clinical data available had multiple lymphadenopathies (25/28, 89%), stage III to IV diseases (17/26, 65%), B symptoms (7/27, 26%), and skin lesions (6/23, 26%). Three patients with sequential biopsies disclosed clinical and histopathologic features of angioimmunoblastic T-cell lymphoma at initial presentation. Our results show that this rare form of PTCL-F (1) has an immunophenotype indicative of derivation from TFH cells, (2) is associated with t(5;9) in a proportion of cases, and (3) shows some overlapping features with angioimmunoblastic T-cell lymphoma, raising the question of a possible relationship.

Published
2009
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11. Assignment of Aegilops variabilis Eig chromosomes and translocations carrying resistance to nematodes in wheat

Author

Jocelyne Lemoine, Joseph Jahier, Anne-Marie Tanguy, Virginie Huteau, Dominique BarloyD. Barloy, Olivier Coriton, Amélioration des Plantes et Biotechnologies Végétales (APBV), AGROCAMPUS OUEST-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-AGROCAMPUS OUEST

Subjects
0106 biological sciences, Nematoda, Introgression, NEMATODE A GALLE, Chromosomal translocation, MESH: Triticum, Biology, Poaceae, MESH: Nematoda, 01 natural sciences, Chromosomes, Plant, Translocation, Genetic, 03 medical and health sciences, MESH: Plant Diseases, Gene mapping, MESH: Poaceae, Genetics, Animals, MESH: Animals, Genetic variability, MESH: Chromosomes, Plant, MESH: In Situ Hybridization, Fluorescence, Triticeae, Molecular Biology, In Situ Hybridization, Fluorescence, Triticum, 030304 developmental biology, Plant Diseases, 2. Zero hunger, 0303 health sciences, INTROGRESSION, Chromosome, food and beverages, General Medicine, biology.organism_classification, SSR, Immunity, Innate, MESH: Translocation, Genetic, MESH: Hybridization, Genetic, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, GISH, Genetic marker, Microsatellite, Hybridization, Genetic, MESH: Immunity, Innate, 010606 plant biology & botany, Biotechnology
Abstract

The allotetraploid species Aegilops variabilis Eig (2n = 28, UUSvSv) belongs to the tribe Triticeae and is closely related to wheat. One accession, Ae. variabilis No. 1, was found to be resistant to the cereal cyst nematode (CCN) and the root-knot nematode (RKN). As the genetic variability for resistance to those two pests is limited within wheat, this accession was crossed to bread wheat. Previous work enabled the development of two addition lines and two translocation lines carrying resistance. Here, we demonstrate, using genomic in situ hybridization, that there is no U–Sv interchange in the parental accession of Ae. variabilis. However, there are multiple rearrangements in the Sv chromosomes. The Ae. variabilis chromosome carrying the CreX gene for resistance to CCN combined segments with homoeology to wheat groups 1, 2, 4, and 6. The CreX gene belongs to the group 1 part and it was likely to have been introduced into chromosome 1BL at a similar location as the previously found QTL QCre.srd-1B for CCN resistance. The second Ae. variabilis chromosome carrying CreY and Rkn2 combined segments with homoeology to wheat groups 2, 4, and 7 on its short arm and group 3 on its long arm. It was designated as 3Sv. The two genes for resistance are carried by its long arm and have been transferred to wheat chromosome 3BL through homoeologous and genetically balanced recombination. Different SSR markers present in the introgressed segments could be used in marker-assisted selection.

Published
2009
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12. T-cell lymphoid aggregates in bone marrow after rituximab therapy for B-cell follicular lymphoma: a marker of therapeutic efficacy?

Author

Diane Damotte, Anne Moreau, Sylvie Caulet-Maugendre, Marie C. Béné, Pascale Cornillet Lefebvre, Martine Patey, Gilles Salles, Marie Christine Rousselet, Jean François Rossi, Pierre Raynaud, Charles Foussard, Antoine Martin, Valérie Costes, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel Dieu, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Haematology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département de Pathologie Cellulaire et Tissulaire, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Rhumatologie, Hôpital de St Brieuc, university hospital, University Hospital, Université de Rennes (UR), Université de Rennes (UR)-Hôpital Pontchaillou, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Hôtel Dieu

Subjects
Male, Pathology, T-Lymphocytes, T-cell infiltration, Follicular lymphoma, Translocation, Genetic, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Follicular, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, Lymphoma, Follicular, MESH: Treatment Outcome, Gene Rearrangement, CD20, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Anti-CD20 monoclonal antibodies, Antibodies, Monoclonal, DNA, Neoplasm, Middle Aged, MESH: Translocation, Genetic, 3. Good health, Survival Rate, Treatment Outcome, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Female, Rituximab, MESH: Bone Marrow, medicine.drug, Adult, medicine.medical_specialty, Bcl2, Lymphoma, B-Cell, MESH: Survival Rate, MESH: Gene Rearrangement, MESH: DNA, Neoplasm, Antineoplastic Agents, Pathology and Forensic Medicine, 03 medical and health sciences, Biopsy, medicine, Humans, Bone marrow, B cell, Aged, 030304 developmental biology, MESH: Lymphoma, B-Cell, Chromosomes, Human, Pair 14, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, MESH: Antineoplastic Agents, MESH: Chromosomes, Human, Pair 14, CD5, Chromosomes, Human, Pair 18, business, MESH: Chromosomes, Human, Pair 18, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Rituximab, an anti-CD20 monoclonal antibody, is widely used in the treatment of B-cell lymphoma. Some reports have outlined histologic modifications in bone marrow specimens from patients treated with this antibody, notably the presence of CD3(+) lymphoid aggregates morphologically mimicking residual lymphoma. To gain insight into the significance of such infiltrates, serial BM trephines obtained in 39 patients with B-cell follicular lymphoma treated by rituximab and enrolled in the GOELAMS-GELA intergroup FL2000 protocol were reexamined. The 39 patients were 22 women and 17 men with a median age of 50 years (range, 29-75 years). All pretreatment bone marrow biopsies showed CD20(+) lymphomatous cells. A second biopsy was obtained between 30 and 100 days after the last rituximab injection: 19 (48%) were morphologically diagnosed as negative (no lymphoid infiltrates or only minor lymphoid aggregates) and 20 (51%) as positive because of persistent lymphoid nodules. After immunohistochemical analysis, 13 (33%) cases were reinterpreted as false-positive because of the complete absence of CD20(+) cells, with the lymphoid nodules consisting of CD3(+) and CD5(+) T cells. Most of them also expressed CD4(+), whereas only a few CD8(+) cells were present. Among these 13 false-positive cases, 12 were BCL2-IGH polymerase chain reaction-negative in the bone marrow aspirate at the time of biopsy. The 13th case turned out to be negative in the 18th-month bone marrow aspirate. In all of these cases, lymphoid aggregates had disappeared on bone marrow biopsies performed 18 months after treatment. After a mean follow-up of 4.5 years, 9 of 13 patients were in remission as compared with only 2 among the 7 patients with postrituximab persistent CD20(+) lymphomatous cells. There was no statistically significant difference between this false-positive group of patients and that with negative postrituximab bone marrow regarding sex, age, medullar involvement pattern before treatment, delay between rituximab treatment, and molecular status. Interestingly, we noted a more favorable outcome (70% versus 52% remission) for the false-positive cases, suggesting that these T-cell reactions could be the hallmark of specific antitumoral immunity after rituximab treatment and should be properly investigated.

Published
2008
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13. In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability

Author

Bertrand Montpellier, Bertrand Nadel, Pierre Ferrier, Immo Prinz, Olivier Cabaud, Jean-Marc Navarro, Elodie Vachez, Katrina Vanura, Trang Le, Rodrig Marculescu, Sandrine Roulland, Ulrich Jäger, Salvatore Spicuglia, Division of Hematology, Medizinische Universität Wien = Medical University of Vienna, 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), This work was supported by the grant ID20010 from the Centre of Molecular Medicine (Austrian Academy of Science), the grant P13984 from the Fonds zur Förderung der Wissenschaftlichen Forschung (FWF), the Austrian GEN-AU GZ 200.136/1-VI/1/2005 project, the grant INE2003114116 from la Fondation pour la Recherche Médicale (FRM), a grant from Le Conseil Général des Bouches du Rhône, and institutional grants from Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National De La Recherche Scientifique (CNRS). Work in the BN lab is supported by the AVENIR2003 grant from INSERM. The PF lab is supported by specific grants from the Association pour la Recherche sur le Cancer (ARC grant 3275) and the Foundation Princesse Grace de Monaco. BN is a recipient of a Contrat d'Interface INSERM/Assistance Publique-Hôpitaux de Marseille. BM is a recipient of a fellowship from la Ligue Nationale Contre le Cancer., Haon, Marie Laure, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Genome instability, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Chromosomal translocation, Biology, medicine.disease_cause, Genome, Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, Genomic Instability, Translocation, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, Recombinase, medicine, Animals, Leukemia-Lymphoma, Adult T-Cell, MESH: Animals, MESH: Leukemia-Lymphoma, Adult T-Cell, Biology (General), VDJ Recombinases, MESH: Mice, Cells, Cultured, 030304 developmental biology, Genetics, Recombination, Genetic, 0303 health sciences, MESH: VDJ Recombinases, General Immunology and Microbiology, General Neuroscience, MESH: Genomic Instability, Synapsis, MESH: Polymerase Chain Reaction, Gene rearrangement, MESH: Translocation, Genetic, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Recombination, Genetic, General Agricultural and Biological Sciences, Carcinogenesis, Ex vivo, 030215 immunology, Research Article, MESH: Cells, Cultured
Abstract

It has long been thought that signal joints, the byproducts of V(D)J recombination, are not involved in the dynamics of the rearrangement process. Evidence has now started to accumulate that this is not the case, and that signal joints play unsuspected roles in events that might compromise genomic integrity. Here we show both ex vivo and in vivo that the episomal circles excised during the normal process of receptor gene rearrangement may be reintegrated into the genome through trans-V(D)J recombination occurring between the episomal signal joint and an immunoglobulin/T-cell receptor target. We further demonstrate that cryptic recombination sites involved in T-cell acute lymphoblastic leukemia–associated chromosomal translocations constitute hotspots of insertion. Eventually, the identification of two in vivo cases associating episomal reintegration and chromosomal translocation suggests that reintegration events are linked to genomic instability. Altogether, our data suggest that V(D)J-mediated reintegration of episomal circles, an event likely eluding classical cytogenetic screenings, might represent an additional potent source of genomic instability and lymphoid cancer., Author Summary Lymphoid cells recognize billions of pathogens as a result of gene rearrangements that generate pathogen-specific B- and T-cell receptors. This genetic reshuffling, called V(D)J recombination, occasionally misfires and damages genomic integrity. When such aberrations dysregulate proto-oncogenes, cancer ensues. It has become increasingly clear that multiple oncogenes acting in different cellular pathways can cooperate to cause cancer. Nevertheless, in the case of T-cell acute lymphoblastic leukemia, about a third of cases display oncogene activation in the absence of identified aberration, suggesting the presence of additional mechanisms of chromosomal alteration. In the hunt for such mechanisms, episomal circles (DNA segments that are excised during V(D)J recombination) have recently drawn attention. Moreover, signal joints, short sequences formed after gene rearrangements, once considered harmless, now appear to take part in events that might compromise genomic integrity. Using ex vivo recombination assays and genetically modified mice, we demonstrate that episomal circles may be reintegrated into the genome through recombination occurring between the episomal signal joints and a T-cell receptor target. Furthermore, we show that cryptic recombination sites located in the vicinity of oncogenes constitute hotspots of episomal insertion. Altogether, our results suggest that reintegration of excised episomal circles constitute a potential source of genomic instability and cancer in leukemia and lymphoma., Episomal DNA circles are the by-products of immunoreceptor gene rearrangements in lymphoid cells. Episomal circles can be reintegrated into the genome by trans-V(D)J recombination and cause oncogene deregulation.

Published
2007
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14. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study

Author

Vey, N., Thomas, X., Picard, C., Kovascovicz, T., Charin, C., Cayuela, J. M., Dombret, H., Dastugue, N., Huguet, F., Bastard, C., Stamatoulas, A., Giollant, M., Tournilhac, O., Macintyre, E., Buzyn, A., Bories, D., Kuentz, M., Dreyfus, F., Delannoy, A., Raynaud, S., Gratecos, N., Bordessoule, Dominique, De Botton, S., Preudhomme, C., Reman, O., Troussard, X., Pigneux, A., Bilhou, C., Vernant, J. P., Boucheix, C., Gabert, J., Renseigné, Non, Laboratoire de chimie et biochimie des substances naturelles, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Danone Research, Groupe DANONE, Recherche & Développement, EDF (EDF), Service greffe de moelle osseuse, Université Paris Diderot - Paris 7 (UPD7)-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), Laboratoire d'oncohématologie, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], Université de Limoges (UNILIM), 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), Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Différenciation hématopoïétique normale et leucémique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]

Subjects
Male, Oncology, Cancer Research, MESH: Chromosomes, Human, Pair 19, medicine.medical_treatment, Translocation, Genetic, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, Prospective Studies, E2a pbx1, Prospective cohort study, Acute leukemia, MESH: Middle Aged, Pre-B-Cell Leukemia Transcription Factor 1, Hematopoietic Stem Cell Transplantation, Nuclear Proteins, hemic and immune systems, Hematology, Middle Aged, Burkitt Lymphoma, MESH: Translocation, Genetic, 3. Good health, DNA-Binding Proteins, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Chromosomes, Human, Pair 4, Transcriptional Elongation Factors, Stem cell, Myeloid-Lymphoid Leukemia Protein, Adult, medicine.medical_specialty, MESH: Chromosomes, Human, Pair 4, Adolescent, MESH: Chromosomes, Human, Pair 1, 03 medical and health sciences, Proto-Oncogene Proteins, Internal medicine, Acute lymphocytic leukemia, medicine, MESH: Transplantation, Homologous, Humans, Transplantation, Homologous, neoplasms, MESH: Hematopoietic Stem Cell Transplantation, MESH: Adolescent, Chemotherapy, MESH: Humans, business.industry, Chromosomes, Human, Pair 11, MESH: Adult, Histone-Lysine N-Methyltransferase, B-cell acute lymphoblastic leukemia, medicine.disease, MESH: Male, MESH: Prospective Studies, Surgery, Transplantation, MESH: Burkitt Lymphoma, MESH: Proto-Oncogene Proteins, MESH: Myeloid-Lymphoid Leukemia Protein, MESH: Chromosomes, Human, Pair 11, business, Chromosomes, Human, Pair 19, MESH: Female, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, 030215 immunology
Abstract

International audience; Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Published
2006
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15. Fluorescence in situ hybridization sperm analysis of six translocation carriers provides evidence of an interchromosomal effect

Author

Michèle Treger, Monique Schillinger, Nadejda Machev, Philippe Gosset, Stéphanie Warter, Stéphane Viville, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Adult, Male, medicine.medical_specialty, MESH: Chi-Square Distribution, Semen, Chromosomal translocation, Biology, MESH: Oligospermia, Translocation, Genetic, 03 medical and health sciences, 0302 clinical medicine, Meiosis, MESH: Uniparental Disomy, medicine, Humans, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Chi-Square Distribution, MESH: Humans, MESH: Middle Aged, medicine.diagnostic_test, MESH: Spermatozoa, Cytogenetics, Obstetrics and Gynecology, Chromosome, Chromosome Mapping, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Oligospermia, Middle Aged, Uniparental Disomy, University hospital, Sperm, Molecular biology, Spermatozoa, MESH: Male, MESH: Translocation, Genetic, 3. Good health, Reproductive Medicine, MESH: Chromosome Mapping, Fluorescence in situ hybridization
Abstract

Objective To investigate the existence of an interchromosomal effect in balanced reciprocal translocation carriers and to evaluate their risk of having an affected child or repeated spontaneous abortions. Design Analysis of chromosomal sperm content by fluorescence in situ hybridization (FISH) using probes for chromosomes 1, 15, 16, 17, 18, X, and Y. Setting University hospital. Patient(s) Six male carriers of balanced chromosome rearrangements, one with normal sperm parameters and five with oligoasthenoteratozoospermia, and seven fertile controls. Intervention(s) Fluorescence in situ hybridization for chromosomal enumeration on sperm samples. Main Outcome Measure(s) Rate of disomy for the studied chromosomes. Result(s) A total of 123,842 spermatozoa were scored (82,181 for controls and 41,661 for patients). For each patient, at least one chromosome studied presented a significantly increased rate of disomy. One patient showed a clear interchromosomal effect for at least three of the six chromosomes studied. Disomy rates were statistically significantly and inversely correlated with the total progressive motility of spermatozoa. Conclusion(s) The observed interchromosomal effect seems to be translocation, patient, and chromosome dependent. Variable effects were observed, according to the chromosome studied. When we looked at patients carrying the same translocation, the level of disomy rate was variable and affected different chromosomes.

Published
2005
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16. Differences in nuclear positioning of 1q12 pericentric heterochromatin in normal and tumor B lymphocytes with 1q rearrangements

Author

Patricia Le Baccon, Leila Barki-Celli, Yves Usson, Saadi Khochbin, Claire Vourc'h, Dominique Leroux, Christine Lefebvre, Mary Callanan, Thierry Bonnefoix, Gwenaël Nadeau, RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)

Subjects
MESH: Hydroxamic Acids, Cancer Research, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Chromosomal translocation, Hydroxamic Acids, Lymphocyte Activation, Translocation, Genetic, MESH: Lymphoma, Follicular, 0302 clinical medicine, Heterochromatin, MESH: In Situ Hybridization, Fluorescence, Receptor, Lymphoma, Follicular, Pericentric heterochromatin, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, B-Lymphocytes, Burkitt Lymphoma, MESH: Translocation, Genetic, Cell biology, MESH: Heterochromatin, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, medicine.drug, MESH: Cell Nucleus, MESH: Cell Line, Tumor, MESH: Chromosomes, Human, Pair 1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Cell Line, Tumor, MESH: B-Lymphocytes, medicine, Constitutive heterochromatin, Humans, MESH: Chromosome Aberrations, Enhancer, MESH: Lymphocyte Activation, 030304 developmental biology, Cell Nucleus, Chromosome Aberrations, MESH: Humans, Histone Deacetylase Inhibitors, MESH: Burkitt Lymphoma, MESH: Histone Deacetylases, Trichostatin A, Histone deacetylase
Abstract

The frequent rearrangement of chromosome band 1q12 constitutive heterochromatin in hematologic malignancies suggests that this rearrangement plays an important pathogenetic role in these diseases. The oncogenic mechanisms linked to 1q12 heterochromatin are unknown. Constitutive heterochromatin can epigenetically regulate gene function through the formation of transcriptional-silencing compartments. Thus, as a first step toward understanding whether 1q12 rearrangements might compromise such activity in tumor cells, we investigated the 3-D organization of the 1q12 heterochromatin domain (1q12HcD) in normal and tumor B lymphocytes. Strikingly, in normal B cells, we showed that the 1q12HcD dynamically organizes to the nuclear periphery in response to B-cell receptor engagement. Specifically, we observed an almost twofold increase in 1q12Hc domains at the extreme nuclear periphery in activated versus resting B lymphocytes. Remarkably, 1q12Hc organization was noticeably altered in tumor cells that showed structural alterations of 1q12; the 1q12Hc domains were significantly displaced from the extreme nuclear periphery compared to normal activated B lymphocytes (P > 0.0001), although overall peripheral localization was maintained. In a case in which there was a translocation of IGL enhancer to 1q, the altered nuclear positioning of the 1q12HcD was even more pronounced (5% of the 1q12Hc domains at the nuclear periphery compared to 20% in other lymphoma lines), and we were able to mimic this effect in two additional B-cell tumor lines by treatment with trichostatin A, a histone deacetylase (HDAC) inhibitor. Taken together, these results point to the 1q12HcD having a specific, nonrandom, and regulated peripheral organization in B lymphocytes. This organization is significantly disrupted in lymphoma cells harboring 1q rearrangements. © 2005 Wiley-Liss, Inc.

Published
2005
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17. Protective anti-V antibodies inhibit Pseudomonas and Yersinia translocon assembly within host membranes

Author

Petr Broz, Julien Goure, Ina Attree, Guy R. Cornelis, Olivier Attree, Biochimie et biophysique des systèmes intégrés (BBSI), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Biozentrum [Basel, Suisse], University of Basel (Unibas), and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
MESH: DNA Primers, Erythrocytes, Yersinia, MESH: Erythrocyte Membrane, Polymerase Chain Reaction, Translocation, Genetic, Microbiology, 03 medical and health sciences, Antigen, medicine, Immunology and Allergy, Humans, LcrV, Secretion, 030304 developmental biology, DNA Primers, 0303 health sciences, MESH: Humans, biology, 030306 microbiology, MESH: Erythrocytes, Cell Membrane, Erythrocyte Membrane, MESH: Yersinia, MESH: Polymerase Chain Reaction, biology.organism_classification, medicine.disease, Translocon, Enterobacteriaceae, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Hemolysis, MESH: Translocation, Genetic, Infectious Diseases, Secretory protein, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, MESH: Cell Membrane
Abstract

International audience; Pathogenic Yersinia species and Pseudomonas aeruginosa share a similar type III secretion/translocation system. The translocation system consists of 3 secreted proteins, YopB/PopB, YopD/PopD, and LcrV/PcrV; the latter is known to be a protective antigen. In an in vitro assay, the translocation system causes the lysis of erythrocytes infected with wild-type (wt) P. aeruginosa. wt Y. enterocolitica is not hemolytic, but a multiknockout mutant deprived of all the effectors and of YopN ( Delta HOPEMN) is hemolytic. In the presence of antibodies against PcrV and Y. pestis LcrV, the hemolytic activity of P. aeruginosa was inhibited. Similarly, the hemolytic activity of Delta HOPEMN was inhibited in the presence of anti-LcrV antibodies. The assembly of the translocon, composed of PopB/D and YopB/D proteins, was disturbed in immunoprotected erythrocyte membranes, mimicking the phenotypes of V knockout mutants. Thus, protective antibodies against the V antigens of Yersinia species and P. aeruginosa act at the level of the formation of the translocon pore in membranes of infected host cells by blocking the function of LcrV/PcrV. The hemolysis assay could be adapted for high-throughput screening of anti-infectious compounds that specifically target the type III translocon.

Published
2005
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18. DLX genes as targets of ALL-1: DLX 2,3,4 down-regulation in t(4;11) acute lymphoblastic leukemias

Author

Laura Paleari, Carlo M. Croce, Giulio Lelio Palmisano, Giovanni Levi, Adriana Albini, Giuseppe Basso, Vincenzo Fidanza, Claudio Brigati, Manuela Mangioni, Nicoletta Ferrari, Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), and Demeneix, Barbara

Subjects
MESH: Neoplasm Proteins, Chromosomal translocation, MESH: Mice, Knockout, Translocation, Genetic, MESH: Down-Regulation, Mice, MESH: Leukemia, Lymphocytic, Acute, MESH: Reverse Transcriptase Polymerase Chain Reaction, Immunology and Allergy, MESH: Animals, RNA, Neoplasm, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, DLX3, Stem Cells, Genes, Homeobox, DLX6, MESH: Transcription Factors, DLX5, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Translocation, Genetic, Neoplasm Proteins, Antigens, Surface, Stem cell, Chromosomes, Human, Pair 4, MESH: DNA Primers, MESH: Chromosomes, Human, Pair 4, MESH: Antigens, Surface, Immunology, Down-Regulation, MESH: Stem Cells, Biology, [SDV.BDD] Life Sciences [q-bio]/Development Biology, MESH: Homeodomain Proteins, Animals, Humans, RNA, Messenger, Gene, MESH: Mice, DNA Primers, MESH: RNA, Messenger, Homeodomain Proteins, MESH: Humans, Chromosomes, Human, Pair 11, MESH: Genes, Homeobox, Cell Biology, MESH: RNA, Neoplasm, Embryonic stem cell, Molecular biology, Cancer research, Homeobox, MESH: Chromosomes, Human, Pair 11, Transcription Factors
Abstract

Dlx genes constitute a gene family thought to be essential in morphogenesis and development. We show here that in vertebrate cells, Dlx genes appear to be part of a regulatory cascade initiated by acute lymphoblastic leukemia (ALL)-1, a master regulator gene whose disruption is implicated in several human acute leukemias. The expression of Dlx2, Dlx3, Dlx5, Dlx6, and Dlx7 was absent in All-1 −/− mouse embryonic stem cells and reduced in All-1 +/− cells. In leukemic patients affected by the t(4;11)(q21;q23) chromosomal abnormality, the expression of DLX2, DLX3, and DLX4 was virtually abrogated. Our data indicate that Dlx genes are downstream targets of ALL-1 and could be considered as important tools for the study of the early leukemic cell phenotype.

Published
2003

19. Identical abnormality of the short arm of chromosome 18 in two Philadelphia-positive chronic myelocytic leukemia patients with erythroblastic transformation, resulting in duplication of BCR-ABL1 fusion

Author

Roland Berger, Michel Arock, Hélène Merle-Béral, Frederic Davi, Florence Nguyen Khac, Antoine Ribadeau-Dumas, Isabelle Radford-Weiss, Maryvonne Busson, Marie Agnès Collonge-Rame, Marie-Claude Piffaut, Marie-Thérèse Daniel, Marie Christine Waill, Serge Romana, Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Différenciation Cellulaire et Croissance (DCC), Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences de l'Information et des Systèmes (LSIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie organique et organométallique (LCOO), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Université de Toulon (UTLN)-Aix Marseille Université (AMU), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Différenciation Cellulaire et Croissance ( DCC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Sciences de l'Information et des Systèmes ( LSIS ), Aix Marseille Université ( AMU ) -Université de Toulon ( UTLN ) -Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique ( CNRS ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de chimie organique et organométallique ( LCOO ), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique ( CNRS ), Institut de Chimie de la Matière Condensée de Bordeaux ( ICMCB ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Service d'hématologie biologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), and École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Cancer Research, Erythrocytes, Chromosomes, Human, Pair 22, bcr-abl, MESH : Aged, MESH : Chromosomes, Human, Pair 22, Fusion Proteins, bcr-abl, Chromosomal translocation, Cell Transformation, Translocation, Genetic, 0302 clinical medicine, MESH: Aged, 80 and over, MESH : Translocation, Genetic, Gene Duplication, hemic and lymphatic diseases, 80 and over, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: In Situ Hybridization, Fluorescence, MESH : Karyotyping, Chronic, MESH: Chromosomes, Human, Pair 22, In Situ Hybridization, Fluorescence, In Situ Hybridization, Aged, 80 and over, Genetics, MESH: Aged, 0303 health sciences, Leukemia, ABL, MESH: Middle Aged, medicine.diagnostic_test, MESH: Erythrocytes, MESH: Gene Duplication, MESH : Chromosomes, Human, Pair 18, MESH : Fusion Proteins, bcr-abl, Middle Aged, MESH: Translocation, Genetic, MESH : In Situ Hybridization, Fluorescence, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Human, MESH : Gene Duplication, MESH : Chromosome Aberrations, Translocation, Blastic Phase, Biology, Philadelphia chromosome, Chromosomes, Fluorescence, 03 medical and health sciences, Genetic, Chromosome 18, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, MESH: Chromosome Aberrations, MESH : Middle Aged, MESH : Aged, 80 and over, Molecular Biology, Aged, 030304 developmental biology, Chromosome Aberrations, Neoplastic, Pair 18, MESH: Humans, MESH: Fusion Proteins, bcr-abl, MESH : Humans, Fusion Proteins, MESH : Cell Transformation, Neoplastic, Gene rearrangement, medicine.disease, Molecular biology, MESH: Karyotyping, MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive, MESH: Cell Transformation, Neoplastic, Karyotyping, MESH : Leukemia, Myelogenous, Chronic, BCR-ABL Positive, BCR-ABL Positive, Pair 22, Chromosomes, Human, Pair 18, MESH: Chromosomes, Human, Pair 18, Chromosome 22, MESH: Female, MESH : Erythrocytes, Myelogenous, Fluorescence in situ hybridization
Abstract

Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic transformation and rearrangement of the short arm of chromosome 18 are reported. Fluorescence in situ hybridization studies showed that the 18p rearrangement resulted from translocation of the main part of chromosome 22 long arm to 18p, including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and duplication of BCR-ABL1 in both patients. The possible relation to the erythroblastic type of blastic phase is briefly discussed. In addition an apparently intact germline ABL1 gene was duplicated and inserted into chromosome 6 at band p21 in one of these patients.

Published
2002

20. A novel automated strategy for screening cryptic telomeric rearrangements in children with idiopathic mental retardation

Author

Laurence Colleaux, Séverine Moindrault, Martine Le Merrer, Odile Raoult, Solange Heuertz, Valérie Cormier-Daire, Stanislas Lyonnet, François Cornelis, Marguerite Prieur, Monique Picq, Philippe Gosset, Catherine Ozilou, Marlène Rio, Serge Romana, Marie-Christine de Blois, Catherine Turleau, Arnold Munnich, Jeanne Amiel, Michel Vekemans, Handicaps génétiques de l'enfant (Inserm U393), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génopole [Evry], Université d'Évry-Val-d'Essonne (UEVE), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], This work was supported by Centre National de la Recherche Scientifique and by Fondation pour la Recherche Médicale, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Non-Mendelian inheritance, MESH: Genetic Markers, Translocation, Genetic, MESH: Genotype, Monosomy, 0302 clinical medicine, MESH: Child, Child, Genetics (clinical), Gene Rearrangement, Genetics, 0303 health sciences, MESH: Genetic Testing, 030305 genetics & heredity, Telomere, Subtelomere, MESH: Monosomy, MESH: Translocation, Genetic, Pedigree, Cytogenetic Analysis, Microsatellite, %22">Fish , Chromosomes, Human, Pair 6, Female, Genetic Markers, Genotype, MESH: Chromosomes, Human, Pair 6, MESH: Pedigree, MESH: Gene Rearrangement, Biology, MESH: Intellectual Disability, 03 medical and health sciences, Intellectual Disability, Humans, Genetic Testing, Genotyping, MESH: Humans, Chromosomes, Human, Pair 10, MESH: Cytogenetic Analysis, MESH: Male, MESH: Karyotyping, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic marker, MESH: Chromosomes, Human, Pair 10, Karyotyping, MESH: Telomere, MESH: Female, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, Uniparental Disomies, MESH: Chromosomes, Human, Pair 16
Abstract

International audience; Cryptic unbalanced subtelomeric rearrangements are known to cause a significant proportion of idiopathic mental retardation in childhood. Because of the limited sensitivity of routine analyses, the cytogenetic detection of such rearrangements requires molecular techniques, namely FISH and comparative genomic hybridisation (CGH). An alternative approach consists in using genetic markers to detect segmental aneusomy. Here, we describe a new strategy based upon automated fluorescent genotyping to search for non mendelian segregation of telomeric microsatellites. A total of 29 individuals belonging to 24 unrelated families were screened and three abnormal patterns of segregation were detected (two rearrangements and one parental disomy). This study gives strong support to the view that cryptic telomeric rearrangements significantly contribute to idiopathic mental retardation and demonstrates that fluorescent genotyping is a very sensitive and cost-effective method to detect deletions, duplications and uniparental disomies.

Published
2001
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21. RNA delivery into mitochondria

Author

Robert P. Martin, Olga Kolesnikova, Nina Entelis, Ivan Tarassov, Reibel, Cathy, Génétique moléculaire, génomique, microbiologie (GMGM), and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Mutation, RNA, Mitochondrial, MESH: Mitochondria, Saccharomyces cerevisiae, MESH: Plants, Pharmaceutical Science, Mitochondrion, Biology, Genome, Translocation, Genetic, RNA, Transfer, MESH: Cholelithiasis, MESH: Sex Factors, MESH: RNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cholecystography, MESH: Age Factors, MESH: Humans, MESH: Middle Aged, Genetic transfer, Tetrahymena, Mitochondrial Myopathies, RNA, Intracellular Membranes, Plants, MESH: Gallbladder Neoplasms, biology.organism_classification, MESH: RNA, Transfer, MESH: Saccharomyces cerevisiae, Yeast, MESH: Translocation, Genetic, MESH: Male, Mitochondria, MESH: Intracellular Membranes, Biochemistry, Cytoplasm, MESH: Mitochondrial Myopathies, Mutation, MESH: Great Britain, MESH: Female
Abstract

Mitochondria, though containing their own genome, import the vast majority of their macromolecular components from the cytoplasm. If the mechanisms of pre-protein import are well understood, the import of nuclear-coded RNAs into mitochondria was investigated to a much lesser extent. This targeting, if not universal, is widely spread among species. The origin and the mechanisms of RNA import seem to differ from one system to another and striking differences are observed even in closely related species. We describe data concerning the various experimental systems of studying RNA import with emphasis on the model of the yeast Saccharomyces cerevisiae, which was studied in our laboratory. We compare various requirements of RNA import into mitochondria in different species and demonstrate that this pathway can be transferred from yeast to human cells, in which tRNAs normally are not imported. We speculate on the possibility to use RNA import for biomedical purposes.

Published
2001

22. A retrovirus carrying the promyelocyte-retinoic acid receptor PML-RARalpha fusion gene transforms haematopoietic progenitors in vitro and induces acute leukaemias

Author

Catherine Lavau, Suk-Chul Bae, Anne Dejean, Madeleine Garcia, Jacques Samarut, Muriel Altabef, Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon), Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC), Region Rhone-Alpes and Ligue Departementale de l'Yonne contre le Cancer to J.S., and from ARC and EEC Biotech and Biomed programs to A.D. M.A. is the recipient of fellowships from the Ministere de la Recherche et de l'Enseignement Superieur and ARC., École normale supérieure de Lyon (ENS de Lyon), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, MESH: Oncogenes, Receptors, Retinoic Acid, viruses, [SDV]Life Sciences [q-bio], MESH: Amino Acid Sequence, Promyelocytic Leukemia Protein, Translocation, Genetic, MESH: Hematopoietic Stem Cells, Fusion gene, 0302 clinical medicine, Retrovirus, MESH: Promyelocytic Leukemia Protein, MESH: Animals, 0303 health sciences, MESH: Retinoic Acid Receptor alpha, biology, leukaemic transformation, General Neuroscience, Retinoic Acid Receptor alpha, MESH: Bone Marrow Cells, MESH: Chickens, Nuclear Proteins, virus diseases, MESH: Transcription Factors, MESH: Translocation, Genetic, Cell biology, Neoplasm Proteins, [SDV] Life Sciences [q-bio], Haematopoiesis, Cell Transformation, Neoplastic, haematopoietic differentiation, 030220 oncology & carcinogenesis, Acute Disease, MESH: Acute Disease, Research Article, Recombinant Fusion Proteins, Molecular Sequence Data, MESH: Leukemia, Experimental, Bone Marrow Cells, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Promyelocytic leukemia protein, MESH: Recombinant Fusion Proteins, Animals, Humans, Point Mutation, MESH: Tumor Suppressor Proteins, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, MESH: Point Mutation, MESH: Receptors, Retinoic Acid, Leukemia, Experimental, MESH: Humans, MESH: Molecular Sequence Data, General Immunology and Microbiology, Tumor Suppressor Proteins, Oncogenes, biology.organism_classification, Hematopoietic Stem Cells, Fusion protein, Molecular biology, Retinoic acid receptor, nuclear hormone receptor, Retinoic acid receptor alpha, MESH: Cell Transformation, Neoplastic, biology.protein, PML-RARa, Chickens, MESH: Nuclear Proteins, Promyelocyte, Transcription Factors
Abstract

International audience; The promyelocyte (PML)-retinoic acid receptor alpha (RARalpha) fusion gene results from a t(15;17) chromosome translocation in acute promyelocytic leukaemia. We have analysed the oncogenic potential of the human fusion PML-RARalpha product in chicken using retrovirus vectors. We show that PML-RARalpha transforms very early haematopoietic progenitor cells in vitro and induces acute leukaemias. Neither PML nor RARalpha domains alone achieve such a transformation. The PML-RARalpha viruses recovered from the transformed cells carry two point mutations in the PML domain, one of which alters both the pattern of intracellular localization of the fusion protein and its functional interference with AP-1, thus defining an essential domain in PML for oncogenic transformation.

Published
1996
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23. Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways

Author

Abderrahim Mahfoudi, Sophie Rambaud, Walter Wahli, Anne Dejean, Joop H. Jansen, Catherine Lavau, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Animale, Université de Lausanne = University of Lausanne (UNIL), This work was supported by the European Economic Community (Biomedical and Biotechnology Programs), the Association pour la Recherche contre le Cancer, the Etat de Vaud, and the Swiss National Science Foundation. J.H.J. was supported by the Human Frontier Science Program Organization., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, MESH: Signal Transduction, Oncogene Proteins, Fusion, Protein Conformation, Receptors, Retinoic Acid, MESH: Drosophila, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Translocation, Genetic, Mice, Estrogen-related receptor alpha, 0302 clinical medicine, MESH: Protein Conformation, Leukemia, Promyelocytic, Acute, MESH: Animals, G alpha subunit, 0303 health sciences, Multidisciplinary, MESH: DNA, Liver X receptor alpha, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, Cell biology, [SDV] Life Sciences [q-bio], Biochemistry, 030220 oncology & carcinogenesis, embryonic structures, MESH: Retinoid X Receptors, Drosophila, Retinoid X receptor beta, Signal Transduction, Research Article, Transcriptional Activation, Retinoid X receptor, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 03 medical and health sciences, Animals, Humans, neoplasms, MESH: Mice, 030304 developmental biology, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, Binding Sites, MESH: Humans, Retinoid X receptor alpha, organic chemicals, DNA, Retinoid X receptor gamma, biological factors, body regions, Retinoid X Receptors, MESH: Binding Sites, Retinoic acid receptor alpha, MESH: HeLa Cells, MESH: Transcriptional Activation, MESH: Chromosomes, Human, Pair 17, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, HeLa Cells, Transcription Factors, MESH: Chromosomes, Human, Pair 15, MESH: Oncogene Proteins, Fusion
Abstract

International audience; The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

Published
1995
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24. Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells

Author

Sophie Rambaud, Anne Dejean, Angus I. Lamond, Maria Carmo-Fonseca, Catherine Lavau, Teresa Carvalho, Karsten Weis, Joop H. Jansen, European Molecular Biology Laboratory [Heidelberg] (EMBL), Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), This work was supported by grants from the European Economic Community, the Association pour la Recherche contre le Cancer, la Fondation pour la Recherche Médicale, the Junta National de InvestigaGao Cientifica. K. W. was supported by the Boehringer lngelheim Fonda., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universidade de Lisboa (ULISBOA)

Subjects
MESH: Neoplasm Proteins, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Retinoic acid, Fluorescent Antibody Technique, Receptors, Cytoplasmic and Nuclear, Nuclear dots, Promyelocytic Leukemia Protein, Translocation, Genetic, chemistry.chemical_compound, MESH: Cell Compartmentation, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH: Promyelocytic Leukemia Protein, MESH: Autoantibodies, MESH: Fluorescent Antibody Technique, Protein PML, 0303 health sciences, biology, Nuclear Proteins, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Retinoid X Receptors, Acute promyelocytic leukemia, MESH: Cell Nucleus, Tretinoin, MESH: Microscopy, Electron, Retinoid X receptor, MESH: Receptors, Cytoplasmic and Nuclear, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, MESH: Tumor Suppressor Proteins, neoplasms, Autoantibodies, 030304 developmental biology, Cell Nucleus, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Tretinoin, MESH: Humans, Tumor Suppressor Proteins, medicine.disease, Cell Compartmentation, MESH: Cell Line, Microscopy, Electron, Cell nucleus, Retinoic acid receptor, Retinoid X Receptors, chemistry, Cancer research, biology.protein, MESH: Chromosomes, Human, Pair 17, MESH: Nuclear Proteins, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) translocation that fuses the retinoic acid receptor alpha (RAR alpha) to a novel gene product, PML. The involvement of RAR alpha is particularly intriguing in view of the efficient therapeutic effect of retinoic acid (RA) in this disease. In this report, we show that PML is specifically localized within a discrete subnuclear compartment corresponding to nuclear bodies recognized by patient autoimmune sera. In APL cells, the PML-RAR alpha hybrid displays an abnormal localization and directs RXR and other nuclear antigens into aberrant structures that are tightly bound to chromatin. This suggests that the hybrid could exert a dominant negative effect by diverting a subset of proteins from their natural sites of action. Interestingly, treatment of APL cells with RA induces a complete relocalization of each of these proteins. We propose that the beneficial role of RA in promoting myeloid differentiation in APL might be related to its ability to restore a normal subnuclear organization.

Published
1994
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25. The PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1

Author

Doucas, Vassilis, Brockes, Jeremy, Yaniv, Moshe, de Thé, Hugues, Dejean, Anne, Virus oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ludwig Institute for Cancer Research, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS), Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the Association pour la Recherche sur le Cancer and the Ligue Nationale contre le Cancer. V.D. was supported by a predoctoral fellowship from the Association pour la Recherche sur le Cancer, and J.P.B. was supported by an exchange fellowship from the Royal Society and the Centre National de la Recherche Scientifique., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, Proto-Oncogene Proteins c-jun, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], MESH: Collagenases, Retinoic acid, Promyelocytic Leukemia Protein, Translocation, Genetic, Transactivation, chemistry.chemical_compound, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH: Chlorocebus aethiops, MESH: Promyelocytic Leukemia Protein, Chlorocebus aethiops, MESH: Animals, Promoter Regions, Genetic, 0303 health sciences, Multidisciplinary, Nuclear Proteins, MESH: Transcription Factors, MESH: Genes, MESH: Translocation, Genetic, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, embryonic structures, Research Article, medicine.drug, Acute promyelocytic leukemia, Recombinant Fusion Proteins, Tretinoin, In Vitro Techniques, Biology, Cell Line, Structure-Activity Relationship, 03 medical and health sciences, MESH: Promoter Regions, Genetic, medicine, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Tumor Suppressor Proteins, Collagenases, 030304 developmental biology, MESH: In Vitro Techniques, MESH: Receptors, Retinoic Acid, MESH: Humans, MESH: Tretinoin, Retinoid X receptor alpha, MESH: Proto-Oncogene Proteins c-jun, Activator (genetics), organic chemicals, Tumor Suppressor Proteins, medicine.disease, Molecular biology, MESH: Cell Line, Retinoic acid receptor, Genes, chemistry, Retinoic acid receptor alpha, MESH: Nuclear Proteins, Transcription Factors
Abstract

International audience; We report here that the fusion of PML, a nuclear protein defined by the t(15;17) chromosomal translocation in acute promyelocytic leukemia, with retinoic acid receptor alpha (RAR alpha) changes the RAR alpha from a retinoic acid (RA)-dependent inhibitor to a RA-dependent activator of AP-1 transcriptional activity. The PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site. Stimulation is dependent on the concentration of RA and its dose-response curve is comparable to that for activation by RAR alpha of transcription on RA-responsive genes. Further, in the absence of RA, a circumstance in which RAR alpha has no effect on AP-1 activity, PML-RAR alpha is an inhibitor. Deletion of the dimerization, transactivation, or DNA-binding domains of c-Jun and removal of the PML dimerization domain in the PML-RAR alpha hybrid abrogates their transcriptional cooperatively. In view of the association between AP-1 activity and hemopoietic differentiation, we suggest that these properties of PML-RAR alpha could contribute to the leukemic phenotype and its response to RA.

Published
1993
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26. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR

Author

Hugues de Thé, Catherine Lavau, Agnès Marchio, Christine Chomienne, Laurent Degos, Anne Dejean, Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants of the Fondation pour la Recherche MBdicale, the Ligue Nationale Francaise contre le Cancer, and the Association pour la Recherche contre la Cancer., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Oligonucleotides, Chromosome Disorders, MESH: Amino Acid Sequence, Promyelocytic Leukemia Protein, MESH: Base Sequence, Polymerase Chain Reaction, Translocation, Genetic, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH: Oligonucleotides, MESH: Promyelocytic Leukemia Protein, Cloning, Molecular, Zinc finger, Protein PML, 0303 health sciences, MESH: Chromosome Disorders, MESH: DNA, Nuclear Proteins, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, embryonic structures, medicine.drug, Transcriptional Activation, Acute promyelocytic leukemia, Molecular Sequence Data, Tretinoin, MESH: Binding, Competitive, MESH: Carrier Proteins, Biology, Binding, Competitive, General Biochemistry, Genetics and Molecular Biology, Gene product, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, MESH: Chromosome Aberrations, MESH: Tumor Suppressor Proteins, MESH: Cloning, Molecular, Amino Acid Sequence, RNA, Messenger, neoplasms, 030304 developmental biology, MESH: RNA, Messenger, Chromosome Aberrations, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Tretinoin, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Tumor Suppressor Proteins, MESH: Polymerase Chain Reaction, DNA, medicine.disease, Molecular biology, Fusion protein, Retinoic acid receptor alpha, biology.protein, MESH: Transcriptional Activation, Carrier Proteins, MESH: Chromosomes, Human, Pair 17, MESH: Nuclear Proteins, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; We have previously shown that the t(15;17) translocation specifically associated with acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) locus to an as yet unknown gene, initially called myl and now renamed PML. We report here that this gene product contains a novel zinc finger motif common to several DNA-binding proteins. The PML-RAR alpha mRNA encodes a predicted 106 kd chimeric protein containing most of the PML sequences fused to a large part of RAR alpha, including its DNA- and hormone-binding domains. In transient expression assays, the hybrid protein exhibits altered transactivating properties if compared with the wild-type RAR alpha progenitor. Identical PML-RAR alpha fusion points are found in several patients. These observations suggest that in APL, the t(15;17) translocation generates an RAR mutant that could contribute to leukemogenesis through interference with promyelocytic differentiation.

Published
1991
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27. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus

Author

Hugues de Thé, Christine Chomienne, Michel Lanotte, Laurent Degos, Anne Dejean, Recombinaison et expression génétique, Institut Pasteur [Paris] (IP)-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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique cellulaire et moléculaire des leucémies, This work was supported by grants from the Fondation pour Ia Recherche Médicale. the Commission of the European Communities, the Ligue Nationale Française contre le Cancer, and the Association pour Ia Recherche contre le Cancer., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Cheriet Rauline, Samia

Subjects
Transcription, Genetic, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Restriction Mapping, Retinoic acid, Chromosomal translocation, MESH: Base Sequence, Polymerase Chain Reaction, Translocation, Genetic, MESH: Nucleic Acid Hybridization, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, Gene expression, MESH: Restriction Mapping, Gene Rearrangement, 0303 health sciences, Multidisciplinary, biology, Nucleic Acid Hybridization, Exons, MESH: Translocation, Genetic, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, MESH: DNA Probes, DNA Probes, MESH: Gene Rearrangement, Molecular Sequence Data, Locus (genetics), MESH: Carrier Proteins, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, RNA, Messenger, neoplasms, 030304 developmental biology, MESH: RNA, Messenger, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Transcription, Genetic, MESH: Polymerase Chain Reaction, Gene rearrangement, medicine.disease, Molecular biology, Retinoic acid syndrome, Retinoic acid receptor, chemistry, biology.protein, Carrier Proteins, MESH: Exons, MESH: Chromosomes, Human, Pair 17, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis.

Published
1990
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