VOLUME ONE HUNDRED AND SEVENTEEN ADVANCES IN IMMUNOLOGY ASSOCIATE EDITORS K. Frank Austen Harvard Medical School, Boston, Massachusetts, USA Tasuku Honjo Kyoto University, Kyoto, Japan Fritz Melchers University of Basel, Basel, Switzerland Jonathan W. Uhr University of Texas, Dallas, Texas, USA Emil R. Unanue Washington University, St. Louis, Missouri, USA VOLUME ONE HUNDRED AND SEVENTEEN ADVANCES IN IMMUNOLOGY Edited by FREDERICK W. ALT Howard Hughes Medical Institute, Boston, Massachusetts, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK 32 Jamestown Road, London, NW1 7BY, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands First edition 2013 Copyright © 2013 Elsevier Inc. 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Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made ISBN: 978-0-12-410524-9 ISSN: 0065-2776 For information on all Academic Press publications visit our website at store.elsevier.com Printed and bound in USA 13 14 15 16 11 10 9 8 7 6 5 4 3 2 1 CONTENTS Contributors vii 1. Mechanisms of Epigenetic Regulation of Leukemia Onset and Progression 1 Panagiotis Ntziachristos, Jasper Mullenders, Thomas Trimarchi, and Iannis Aifantis 1. Introduction 2 2. Aberrant DNA Methylation in Leukemia 6 3. Disruption of Histone-Modifying Complexes Polycomb and MLL in Leukemia 14 4. Other Epigenetic Writers, Erasers, and Readers 19 5. Novel Aspects and Technologies in Epigenetics: Implications for Leukemia 25 Acknowledgments 27 References 28 2. Translocations in Normal B Cells and Cancers: Insights from New Technical Approaches 39 Roberto Chiarle 1. Mechanistic Elements that Generate Chromosomal Translocations 40 2. Novel High-Throughput Methods to Study Chromosomal Translocations 50 3. New Findings on Translocation Formation Obtained by HTGTS and TC-Seq 52 4. Landscape of Translocations in Cancers 57 5. Perspectives 63 Acknowledgments 64 References 64 3. The Intestinal Microbiota in Chronic Liver Disease 73 Jorge Henao-Mejia, Eran Elinav, Christoph A. Thaiss, and Richard A. Flavell 1. Introduction 74 2. Role of the Intestinal Microbiota on Chronic Liver Diseases 75 3. Role of the Interactions Between the Innate Immune System and the Intestinal Microbiota on Chronic Liver Diseases 81 4. Probiotics and their Potential Role in Liver Disease Therapy 89 v vi Contents 5. Conclusions 90 References 91 4. Intracellular Pathogen Detection by RIG-I-Like Receptors 99 Evelyn Dixit and Jonathan C. Kagan 1. General Principles of the Antiviral Innate Immune Response 99 2. RLRs are RNA Sensors 101 3. RIG-I Activation and Receptor Proximal Signal Propagation 109 4. Regulatory Mechanisms of RIG-I Signaling 113 5. Conclusions and Future Directions 117 Acknowledgments 118 References 118 Index 127 Contents of Recent Volumes 133 CONTRIBUTORS Iannis Aifantis Howard Hughes Medical Institute; Department of Pathology, New York University School of Medicine; NYU Cancer Institute, New York University School of Medicine, and Helen and Martin S. Kimmel Stem Cell Center, New York University School of Medicine, New York, USA Roberto Chiarle Department of Pathology, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA, and Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy Evelyn Dixit Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital, Boston, Massachusetts, USA Eran Elinav Immunology Department, Weizmann Institute of Science, Rehovot, Israel Richard A. Flavell Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, and Howard Hughes Medical Institute, Chevy Chase, Maryland, USA Jorge Henao-Mejia Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA Jonathan C. Kagan Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital, Boston, Massachusetts, USA Jasper Mullenders Howard Hughes Medical Institute; Department of Pathology, New York University School of Medicine; NYU Cancer Institute, New York University School of Medicine, and Helen and Martin S. Kimmel Stem Cell Center, New York University School of Medicine, New York, USA Panagiotis Ntziachristos Howard Hughes Medical Institute; Department of Pathology, New York University School of Medicine; NYU Cancer Institute, New York University School of Medicine, and Helen and Martin S. Kimmel Stem Cell Center, New York University School of Medicine, New York, USA Christoph A. Thaiss Immunology Department, Weizmann Institute of Science, Rehovot, Israel Thomas Trimarchi Howard Hughes Medical Institute; Department of Pathology, New York University School of Medicine; NYU Cancer Institute, New York University School of Medicine, and Helen and Martin S. Kimmel Stem Cell Center, New York University School of Medicine, New York, USA vii Intentionally left as blank CHAPTER ONE Mechanisms of Epigenetic Regulation of Leukemia Onset and Progression Panagiotis Ntziachristos*,†,‡,},1, Jasper Mullenders*,†,‡,},1, Thomas Trimarchi*,†,‡,}, Iannis Aifantis*,†,‡,},2 *Howard Hughes Medical Institute, New York, USA †Department of Pathology, New York University School of Medicine, New York, USA ‡NYU Cancer Institute, New York University School of Medicine, New York, USA }Helen and Martin S. Kimmel Stem Cell Center, New York University School of Medicine, New York, USA 1These authors contributed equally to this work 2Corresponding author: e-mail address: [email protected] Contents 1. Introduction 2 1.1 Leukemia as a heterogeneous and multifactorial disease 2 1.2 Epigenetic factors and their possible roles in leukemia 4 2. Aberrant DNA Methylation in Leukemia 6 2.1 The role of DNA methylation in hematopoietic malignancies 6 2.2 The role of DNMT3A in leukemia 7 2.3 The biology of TET proteins and their perturbations in leukemia 10 2.4 IDH1 and IDH2 oncometabolic proteins 12 3. Disruption of Histone-Modifying Complexes Polycomb and MLL in Leukemia 14 3.1 PRC2 in hematological neoplasms 14 3.2 Role of PRC1 in leukemia 17 3.3 MLL function 17 4. Other Epigenetic Writers, Erasers, and Readers 19 4.1 Arginine methyltransferases 19 4.2 Lysine demethylases (KDMs) 21 4.3 Histone demethylases inhibitors (KDMi) 22 4.4 Histone acetyl transferases 22 4.5 Histone deacetylases 23 4.6 Bromodomain-containing proteins 24 4.7 Plant homeodomain-containing proteins 24 4.8 Chromatin remodeling complexes 25 5. Novel Aspects and Technologies in Epigenetics: Implications for Leukemia 25 5.1 Combinatorial epigenetic marks 25 5.2 Novel aspects of regulation and epigenetic factors in cancer 26 Acknowledgments 27 References 28 Advances in Immunology, Volume 117 # 2013 Elsevier Inc. 1 ISSN 0065-2776 All rights reserved. http://dx.doi.org/10.1016/B978-0-12-410524-9.00001-3 2 Panagiotis Ntziachristos et al. Abstract Over the past decade, it has become clear that both genetics and epigenetics play pivotal roles in cancer onset and progression. The importance of epigenetic regulation in proper maintenance of cellular state is highlighted by the frequent mutation of chromatin mod- ulating factors across cancer subtypes. Identification of these mutations has created an interest in designing drugs that target enzymes involved in DNA methylation and post- translational modification of histones. In this review, we discuss recurrent genetic alter- ations to epigenetic modulators in both myeloid and lymphoid leukemias. Furthermore, we review how these perturbations contribute to leukemogenesis and impact disease outcome and treatment efficacy. Finally, we discuss how the recent advances in our understanding of chromatin biology may impact treatment of leukemia. 1. INTRODUCTION 1.1. Leukemia as a heterogeneous and multifactorial disease Hematopoietic malignancies are a broad category of diseases (Gilliland, 2001). Leukemia is one of the most aggressive among them and is charac- terized as the abnormal proliferation of immature cells of the hematopoietic system. Different types of leukemias can arise from lymphocytes (lympho- cytic leukemia), myeloid cells (myeloid leukemia), erythrocytes (erythro- cytic leukemia), and others in the bone marrow, lymph nodes, or spleen. Regardless of the cell type of origin, leukemia generally proceeds in either a chronic or an acute manner. Chronic disease consists of a long incubation period,