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1. Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors

Author

Marie‐Ange Lespinasse, Kaiyao Wei, Justine Perrin, Matthias Winkler, Sieme Hamaidia, Alexis Leroy, Zuzana Macek Jilkova, Christian Philouze, Patrice N. Marche, Carlo Petosa, Jérôme Govin, Anouk Emadali, Yung‐Sing Wong, Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Département de Chimie Moléculaire (DCM), ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-18-CE18-0007,InhiBET,Développement de nouvelles molécules antifongiques ciblant les protéines BET(2018), wong, yung-sing, Grenoble, une chimie bio-motivée - - ARCANE2011 - ANR-11-LABX-0003 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, and APPEL À PROJETS GÉNÉRIQUE 2018 - Développement de nouvelles molécules antifongiques ciblant les protéines BET - - InhiBET2018 - ANR-18-CE18-0007 - AAPG2018 - VALID

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Organic Chemistry, Stereoisomerism, Antineoplastic Agents, General Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [CHIM.ORGA] Chemical Sciences/Organic chemistry, anti-inflammatory agent, Catalysis, tetrahydroquinoline, BET bromodomain inhibitor, Quinolines, za-ortho-quinone methide, organocatalysis
Abstract

International audience; The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF3.OEt2, which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect.

Published
2022

2. CYCLON and NPM1 Cooperate within an Oncogenic Network Predictive of R-CHOP Response in DLBCL

Author

Tatiana Raskovalova, Edwige Col, Caroline Algrin, Marie-Christine Jacob, Cyril Fournier, Anne McLeer, Anouk Emadali, Samuel Duley, Romain Aucagne, Antonin Bouroumeau, Mary Callanan, Claire Vettier, Hervé Sartelet, Christine Lefebvre, Patricia Betton-Fraisse, Thierry Bonnefoix, Yohann Couté, Lucile Bussot, Andrea Garcìa-Sandoval, Sieme Hamaidia, Annie Adrait, Simon Chevalier, Laurence David-Boudet, Anna Bergan-Dahl, Remy Gressin, Sylvain Carras, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpitaux Universitaires de Genève (HUG), Centre Hospitalier Universitaire [Grenoble] (CHU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut Daniel Hollard [Grenoble], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and Bruley, Christophe

Subjects
Oncology, Cancer Research, medicine.medical_specialty, NPM1, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Article, immune system diseases, Internal medicine, hemic and lymphatic diseases, medicine, CYCLON, nucleolus, R-CHOP, prognosis, R-IPI, Nuclear protein, Adverse effect, RC254-282, Rna processing, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Immunotherapy, medicine.disease, Lymphoma, [SDV] Life Sciences [q-bio], Immunohistochemistry, business
Abstract

Simple Summary CYCLON is a nuclear protein, which has been associated with disease progression and treatment resistance in DLBCL, the most common form of aggressive B-cell lymphoma, but also represents a predictive factor of refractory disease and relapse for immuno-chemotherapy-treated DLBCL patients. The molecular mechanisms related to this unstructured protein remain largely uncharacterized. Here, we performed a mass-spectrometry-based identification of the CYCLON protein interactome that suggested it could exert nucleolar functions related to cell proliferation. Among the CYCLON oncogenic network, we performed an immunohistochemical evaluation of the multi-functional nucleolar protein NPM1 in a DLBCL cohort and showed that CYCLON/NPM1 concomitant expression delineates a poor prognosis subgroup of patients. Multivariate survival analyses demonstrated that specific sub-cellular localizations of CYCLON and NPM1 represent independent novel predictors specifically associated with refractory DLBCL. Abstract R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.

Published
2021

3. Identification of a novel <scp>BET</scp> bromodomain inhibitor‐sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers

Author

Benoit Bernay, Dominique Leroux, Elena Ferri, Florence Combes, Mary Callanan, Remy Gressin, Jérôme Garin, Patricia Betton, Juliana Bruder‐Costa, Sieme Hamaidia, Sophie Rousseaux, Charles E. McKenna, Carlo Petosa, Myriam Ferro, Claire Rome, Anouk Emadali, Samuel Duley, Christophe Bruley, Sylvie Kieffer-Jaquinod, Alexandra Debernardi, and Saadi Khochbin

Subjects
0303 health sciences, Gene knockdown, Cellular differentiation, Biology, medicine.disease, BCL10, 3. Good health, Bromodomain, Lymphoma, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Immunology, medicine, Cancer research, Molecular Medicine, Gene silencing, Rituximab, Epigenetic therapy, 030304 developmental biology, medicine.drug
Abstract

Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.

Published
2013

4. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Author

Florence Nguyen-Khac, Sophie Park, Isabelle Templier, Martine Chauvet, Joel Plumas, Julie Charles, Dominique Leroux, Christine Lefebvre, Sophie Rousseaux, Sieme Hamaidia, François-Loïc Cosset, Els Verhoeyen, Mary Callanan, Dominique Penther, Marie-Christine Jacob, Thierry Bonnefoix, Isabelle Luquet, Sarah Bertrand, Anne Roggy, Cornelis P. Tensen, Elizabeth Macintyre, Anouk Emadali, Neda Hoghoughi, Elisabeth Brambilla, Remy Gressin, Laurence Chaperot, Azadeh Hajmirza, Takahiro Maeda, Christophe Roumier, Philippe Bertrand, Céline Suchaud-Martin, Francine Garnache, Christian Bastard, Samuel Duley, Cristina Mecucci, Fabrice Jardin, Juliana Bruder-Costa, Véronique Josserand, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), CHU de Grenoble-Alpes, Graduate School of Biomedical Sciences [Nagasaki University, Japan], Nagasaki University, Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Leiden University Medical Center (LUMC), Perugia University School of Medicine, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), Universiteit Leiden, Università degli Studi di Perugia = University of Perugia (UNIPG), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté]), and Groupe hospitalier Pitié- Salpêtrière, AP-HP

Subjects
0301 basic medicine, Adult, Skin Neoplasms, Adolescent, Immunology, Plasmacytoid dendritic cell, Haploinsufficiency, Biology, Biochemistry, 03 medical and health sciences, Young Adult, Receptors, Glucocorticoid, medicine, Tumor Cells, Cultured, Humans, Neoplasm Invasiveness, Child, Gene, Aged, Genetics, Regulation of gene expression, Aged, 80 and over, Leukemia, Myeloid Neoplasia, Gene Expression Regulation, Leukemic, Point mutation, hemic and immune systems, Hematology, Cell Biology, Dendritic Cells, Middle Aged, medicine.disease, Non-coding RNA, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Gene expression profiling, stomatognathic diseases, 030104 developmental biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA, Long Noncoding
Abstract

International audience; Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressiveleukemia for which knowledge on disease mechanisms and effective therapies are currentlylacking. Only a handful of recurring genetic mutations have been identified and none isspecific to BPDCN. In this study, through molecular cloning in an index case that presenteda balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, weidentify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR),in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiencyfor NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely pooroverall survival (P 5 .0006). Consistent with a role for GCR in tumor suppression, functionalanalyses coupled with gene expression profiling identified corticoresistance and loss-ofEZH2 function as major downstream consequences of NR3C1 deletion in BPDCN.Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to along noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncodingRNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F.Overexpression oflincRNA-3qwas a consistent feature ofmalignant cells and could be abrogated by bromodomain and extraterminal domain(BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN andidentifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (

Published
2016

5. Cloned IGH VDJ targets as tools for personalized minimal residual disease monitoring in mature lymphoid malignancies; a feasibility study in mantle cell lymphoma by the Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang

Author

Christine Formisano-Tréziny, Jean Gabert, Laetitia Rabin, Eric Voog, Olivier Tournilhac, Steven Le Gouill, Sieme Hamaidia, Mary Callanan, Marie C. Béné, Isabelle Puteaud, Marie Christine Jacob, Martine Chauvet, Juliana Bruder, Estelle Gimenez, Samuel Duley, Hervé Maisonneuve, Remy Gressin, Dominique Leroux, and Valérie Rolland-Neyret

Subjects
Adult, Male, Neoplasm, Residual, Mature B-Cell, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Lymphoma, Mantle-Cell, Biology, Real-Time Polymerase Chain Reaction, Disease-Free Survival, Autologous stem-cell transplantation, hemic and lymphatic diseases, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Stage (cooking), Aged, Hematology, DNA, Neoplasm, Middle Aged, medicine.disease, Prognosis, Minimal residual disease, Peripheral blood, V(D)J Recombination, Real-time polymerase chain reaction, Immunology, Cancer research, Feasibility Studies, Rituximab, Mantle cell lymphoma, Female, Immunoglobulin Heavy Chains, medicine.drug, Plasmids
Abstract

Summary Molecular minimal residual disease (MRD) analysis is fast emerging as an essential clinical decision-making tool for the treatment and follow-up of mature B cell malignancies. Current EuroMRD consensus IGH real-time quantitative polymerase chain reaction RQ-PCR assays rely on flow cytometric assessment of diagnostic tumour burdens to construct ‘normalized’, patient-specific, diagnostic DNA-based MRD quantification standards. Here, we propose a new ‘hybrid’ assay that relies on plasmid-based quantification of patient-specific IGH VDJ targets by consensus IGH real time (RQ)-PCR, combined with EuroMRD guidelines, for MRD monitoring in lymphoid malignancies. This assay was evaluated for MRD assessment in a total of 273 samples from 29 mantle cell lymphoma (MCL) patients treated within a Groupe Ouest Est d'Etude des Leucemies et Autres Maladies du Sang (GOELAMS) Phase II trial and was feasible, reliable and consistently comparable to gold-standard MRD techniques (99% concordance across all samples including 32 samples within the quantitative range) when analysed in parallel (117 samples). Integrating clinical prognostic parameters and MRD status in peripheral blood at the post-induction stage was predictive of progression-free survival (P = 0·034) thus demonstrating the clinical utility of the approach. Plasmid-based standards for the quantification of IGH VDJ targets are therefore confirmed to offer new opportunities for further standardization and clinical evaluation of MRD-guided management of patients with mature B cell malignancies.

Published
2011

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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