ALBERT

Description: Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha1 subunit of soluble guanylyl cyclase (alpha1-sGC), and CCT7 encodes CCTeta, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce alpha1-sGC as well as beta1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in alpha1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erdmann, Jeanette -- Stark, Klaus -- Esslinger, Ulrike B -- Rumpf, Philipp Moritz -- Koesling, Doris -- de Wit, Cor -- Kaiser, Frank J -- Braunholz, Diana -- Medack, Anja -- Fischer, Marcus -- Zimmermann, Martina E -- Tennstedt, Stephanie -- Graf, Elisabeth -- Eck, Sebastian -- Aherrahrou, Zouhair -- Nahrstaedt, Janja -- Willenborg, Christina -- Bruse, Petra -- Braenne, Ingrid -- Nothen, Markus M -- Hofmann, Per -- Braund, Peter S -- Mergia, Evanthia -- Reinhard, Wibke -- Burgdorf, Christof -- Schreiber, Stefan -- Balmforth, Anthony J -- Hall, Alistair S -- Bertram, Lars -- Steinhagen-Thiessen, Elisabeth -- Li, Shu-Chen -- Marz, Winfried -- Reilly, Muredach -- Kathiresan, Sekar -- McPherson, Ruth -- Walter, Ulrich -- CARDIoGRAM -- Ott, Jurg -- Samani, Nilesh J -- Strom, Tim M -- Meitinger, Thomas -- Hengstenberg, Christian -- Schunkert, Heribert -- British Heart Foundation/United Kingdom -- England -- Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S937 Paris, France [3]. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany [3]. ; Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Physiologie, Universitat zu Lubeck, 23562 Lubeck, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany. ; 1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland. ; 1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany. ; Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany. ; Institute of Clinical Molecular Biology, Christian-Albrecht-Universitat, 24105 Kiel, Germany. ; Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Charite Research Group on Geriatrics, Charite-Universitatsmedizin, 10117 Berlin, Germany. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany [2] Department of Psychology, TU Dresden, 01062 Dresden, Germany. ; 1] Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria [3] Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. ; The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02215, USA. ; University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada. ; 1] Centrum fur Thrombose und Hamostase (CTH), Universitatsmedizin Mainz, 55131 Mainz, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany. ; 1] Institute of Psychology, Chinese Academy of Sciences, Beijing 100864, China [2] Laboratory of Statistical Genetics, Rockefeller University, New York 10065, USA. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24213632" target="_blank"〉PubMed〈/a〉

Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opitz, Christiane A -- Litzenburger, Ulrike M -- Sahm, Felix -- Ott, Martina -- Tritschler, Isabel -- Trump, Saskia -- Schumacher, Theresa -- Jestaedt, Leonie -- Schrenk, Dieter -- Weller, Michael -- Jugold, Manfred -- Guillemin, Gilles J -- Miller, Christine L -- Lutz, Christian -- Radlwimmer, Bernhard -- Lehmann, Irina -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21976023" target="_blank"〉PubMed〈/a〉

Description: Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Tae-Won -- Yevsa, Tetyana -- Woller, Norman -- Hoenicke, Lisa -- Wuestefeld, Torsten -- Dauch, Daniel -- Hohmeyer, Anja -- Gereke, Marcus -- Rudalska, Ramona -- Potapova, Anna -- Iken, Marcus -- Vucur, Mihael -- Weiss, Siegfried -- Heikenwalder, Mathias -- Khan, Sadaf -- Gil, Jesus -- Bruder, Dunja -- Manns, Michael -- Schirmacher, Peter -- Tacke, Frank -- Ott, Michael -- Luedde, Tom -- Longerich, Thomas -- Kubicka, Stefan -- Zender, Lars -- MC_U120085810/Medical Research Council/United Kingdom -- England -- Nature. 2011 Nov 9;479(7374):547-51. doi: 10.1038/nature10599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080947" target="_blank"〉PubMed〈/a〉

Description: Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Galpha12 and Galpha13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Galpha13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Galpha13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Galpha13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Galpha13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Galpha13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Galpha13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Galpha13. These findings identify a Galpha13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267955/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267955/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muppidi, Jagan R -- Schmitz, Roland -- Green, Jesse A -- Xiao, Wenming -- Larsen, Adrien B -- Braun, Sterling E -- An, Jinping -- Xu, Ying -- Rosenwald, Andreas -- Ott, German -- Gascoyne, Randy D -- Rimsza, Lisa M -- Campo, Elias -- Jaffe, Elaine S -- Delabie, Jan -- Smeland, Erlend B -- Braziel, Rita M -- Tubbs, Raymond R -- Cook, J R -- Weisenburger, Dennis D -- Chan, Wing C -- Vaidehi, Nagarajan -- Staudt, Louis M -- Cyster, Jason G -- AI45073/AI/NIAID NIH HHS/ -- GM097261/GM/NIGMS NIH HHS/ -- R01 AI045073/AI/NIAID NIH HHS/ -- R01 GM097261/GM/NIGMS NIH HHS/ -- T32 CA128583/CA/NCI NIH HHS/ -- T32 CA1285835/CA/NCI NIH HHS/ -- T32 DK007636/DK/NIDDK NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):254-8. doi: 10.1038/nature13765. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Department of Medicine, University of California, San Francisco, California 94143, USA [3] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA. ; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA [3] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA. ; 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA. ; Department of Pathology, University of Wurzburg, 97080 Wurzburg, Germany. ; 1] Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany [2] Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany. ; British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA. ; Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain. ; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway. ; 1] Institute for Cancer Research, Rikshospitalet University Hospital, University of Oslo, 0310 Oslo, Norway [2] Center for Cancer Biomedicine, Faculty Division of the Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway. ; Oregon Health and Science University, Portland, Oregon 97239, USA. ; Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio 44195, USA. ; Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA. ; 1] Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA [2] Department of Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274307" target="_blank"〉PubMed〈/a〉

Description: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schumacher, Theresa -- Bunse, Lukas -- Pusch, Stefan -- Sahm, Felix -- Wiestler, Benedikt -- Quandt, Jasmin -- Menn, Oliver -- Osswald, Matthias -- Oezen, Iris -- Ott, Martina -- Keil, Melanie -- Balss, Jorg -- Rauschenbach, Katharina -- Grabowska, Agnieszka K -- Vogler, Isabel -- Diekmann, Jan -- Trautwein, Nico -- Eichmuller, Stefan B -- Okun, Jurgen -- Stevanovic, Stefan -- Riemer, Angelika B -- Sahin, Ugur -- Friese, Manuel A -- Beckhove, Philipp -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2014 Aug 21;512(7514):324-7. doi: 10.1038/nature13387. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3]. ; 1] Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany. ; 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; 1] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Ribological GmbH, 55131 Mainz, Germany. ; Translational Oncology, 55131 Mainz, Germany. ; Department of Immunology, University of Tubingen, 72076 Tubingen, Germany. ; Metabolic Centre Heidelberg, University Children's Hospital, 69120 Heidelberg, Germany. ; Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043048" target="_blank"〉PubMed〈/a〉

Description: In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McCabe, Michael T -- Ott, Heidi M -- Ganji, Gopinath -- Korenchuk, Susan -- Thompson, Christine -- Van Aller, Glenn S -- Liu, Yan -- Graves, Alan P -- Della Pietra, Anthony 3rd -- Diaz, Elsie -- LaFrance, Louis V -- Mellinger, Mark -- Duquenne, Celine -- Tian, Xinrong -- Kruger, Ryan G -- McHugh, Charles F -- Brandt, Martin -- Miller, William H -- Dhanak, Dashyant -- Verma, Sharad K -- Tummino, Peter J -- Creasy, Caretha L -- England -- Nature. 2012 Dec 6;492(7427):108-12. doi: 10.1038/nature11606. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051747" target="_blank"〉PubMed〈/a〉