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    Epigenetic Mechanisms in Cancer
    Epigenetic Mechanisms in Cancer
    Epigenetic Mechanisms in Cancer
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    Epigenetic Mechanisms in Cancer

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    Epigenetic Mechanisms in Cancer provides a comprehensive analysis of epigenetic signatures that govern disease development, progression and metastasis. Epigenetic signatures dictating tumor etiologies present an opportunity for biomarker identification which has broad potential for improving diagnosis, prognosis, prediction, and risk assessment. This volumes offers a unique evaluation of signature differences in childhood, sex-specific and race-specific cancers, and in doing so broadly illuminates the scope of epigenetic biomarkers in clinical environments. Chapters detail the major epigenetic process in humans consisting of DNA methylation, histone modifications and microRNAs (miRNAs) involved in the initiation, progression and metastasis of tumors. Also delineated are recent technologies such as next generation sequencing that are used to identify epigenetic profiles (primarily methylation analysis) in samples (normal, benign and cancerous) and which are highly important to the analysis of epigenetic outcomes.
    • Offers broad coverage that is applicable to audiences in various area of cancer research - population studies, diagnostics, prognosis, prediction, therapy, risk, etc.
    • Provides critical review analysis of the topics that will clarify and delineate the potential roles of epigenetic signatures in cancer management
    • Covers basic, as well as, clinical areas of epigenetic mechanisms in tumorigenesis
    • Features contributions by leading experts in the field
    • Provides comprehensive coverage of current epigenetic signatures involved in the etiology of various cancers and miRNAs
    LanguageEnglish
    PublisherAcademic Press
    Release dateNov 16, 2017
    ISBN9780128134603
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      Book preview

      Epigenetic Mechanisms in Cancer - Sabita Saldanha

      Epigenetic Mechanisms in Cancer

      Volume Three

      Editor

      Sabita Saldanha

      Table of Contents

      Cover image

      Title page

      Translational Epigenetics Series

      Copyright

      List of Contributors

      Chapter 1. Epigenetic Dysregulation in Pediatric Leukemia

      1. Introduction

      2. DNA Methylation

      3. Histone Modification

      4. MicroRNA Alterations

      5. Therapeutic Implications and Future Directions

      6. Conclusion

      Chapter 2. Role of Epigenetics in Testicular Cancer

      1. Introduction

      2. Testicular Cancer

      3. Epigenetic Processes: From Normal Spermatogenesis to Testicular Germ Cell Tumors

      4. Therapy Issues: Epigenetic Influence and Resistance to Treatment

      5. Conclusion

      List of Acronyms and Abbreviations

      Glossary

      Chapter 3. Changes in the Epigenetic Landscape of Prostate Cancer

      1. Introduction

      2. Epigenetics of the Biology of the Prostate

      3. Epigenetic Changes in Prostate Cancer

      4. Epigenetic Therapeutics

      5. Summary

      List of Acronyms and Abbreviations

      Glossary

      Chapter 4. The Genetics and Epigenetics of Colorectal Cancer Health Disparity

      1. Introduction

      2. Colorectal Cancer Types

      3. Colorectal Cancer Gene-Based Disparity

      4. Epigenetic Modifications and Colorectal Cancer

      5. Biomarkers of Colorectal Cancer Diagnosis and Prognosis

      6. Conclusion

      List of Abbreviations

      Chapter 5. Genetic and Epigenetic Modifications in Pancreatic Cancer

      1. Introduction

      2. The Genetics/Epigenetics of Pancreatic Cancer

      3. Novel Biomarkers in Pancreatic Cancer

      4. Novel Biomarkers for the Noninvasive Diagnosis of Pancreatic Cancer

      5. Multidisciplinary Management of Metastatic Pancreatic Cancer

      6. Current Perspectives and Future Trends of Systemic Therapy in Advanced Pancreatic Carcinoma

      7. Conclusion

      List of Abbreviations

      Chapter 6. Epigenetics of Breast Cancer

      1. Introduction

      2. DNA Methylation

      3. Breast Cancer

      4. Conclusion

      List of Abbreviations

      Chapter 7. Epigenetic Modulations in Ovarian Cancer

      1. Introduction

      2. Epigenetic Aberrations in Ovarian Cancer

      3. Epigenetic Associated Genes in Ovarian Cancer

      4. Epigenetic Oncogenes Promoting Ovarian Cancer

      5. Epigenetics of Ovarian Cancer–Initiating Cells

      6. Epigenetics Changes and Drug Resistance in Ovarian Cancer

      7. Biomarkers and Epigenetic Therapies for Ovarian Cancer

      8. Current Status of Epigenetic Therapies in Ovarian Cancer

      9. Conclusion

      List of Abbreviations

      Chapter 8. Epigenetic Epidemiology for Cancer Risk

      1. Introduction

      2. Study Design

      3. Tissue-Specificity of Epigenetic Marks

      4. Environmental Exposures

      5. Early Life Exposures

      6. Transgenerational Inheritance of Risk

      7. Epigenetic Dysregulation of Oncogenes and Tumor-Suppressor Genes

      8. Integrated Models

      9. Mitochondrial Epigenetics

      10. Future Directions

      11. Conclusion

      List of Abbreviations

      Chapter 9. Epigenetic Biomarkers in Cancer Epidemiology

      1. Introduction

      2. Cancer Epidemiology and the Role of Biomarkers

      3. Sources of Biomarkers in Cancer Research

      4. Epigenetic Alterations as Cancer Biomarkers: DNA Methylation, miRNA, and Histone Modification

      5. Conclusion

      List of Abbreviations

      Chapter 10. Epigenetic Biomarkers and Racial Differences in Cancer

      1. Introduction

      2. Epigenetic Alterations Associated With Cancer Disparities

      3. Conclusion

      List of Acronyms and Abbreviations

      Chapter 11. Predictive Value of Epigenetic Signatures

      1. Introduction: Epigenetic Traits as New Predictive Biomarkers in Solid Tumors

      2. Predictive Biomarker Validation Strategies

      3. DNA-Methylation-based Predictive Biomarkers

      4. Lung Cancer

      5. Noncoding RNA as Novel Predictive Biomarkers in Cancer

      6. Conclusion and Future Directions

      List of Abbreviations

      Chapter 12. Epigenetic Signatures in the Diagnosis and Prognosis of Cancer

      1. Introduction

      2. A Brief Overview of Epigenetic Mechanisms

      3. Lung Cancer

      4. Breast and Ovarian Cancers

      5. Colorectal Cancer

      6. Prostate Cancer

      7. Stomach Cancer

      8. Cervix and Corpus Uteri Cancer

      9. Liver Cancer

      10. Bladder Cancer

      11. Childhood Leukemia

      12. Conclusion

      List of Acronyms and Abbreviations

      Glossary

      Chapter 13. Future Challenges and Prospects for the Role of Epigenetic Mechanisms in Cancer Management

      1. Introduction to Cancer Management

      2. Role of Epigenetic Signatures in Cancer Treatment

      3. Techniques Involved in the Determination of Epigenetic Signatures (Table 13.1)

      4. Epigenetic Targets and Cancer Management Issues

      5. Future Directions

      List of Abbreviations

      Index

      Translational Epigenetics Series

      Trygve O. Tollefsbol

      Series Editor

      Transgenerational Epigenetics

      Edited by Trygve O. Tollefsbol, 2014

      Personalized Epigenetics

      Edited by Trygve O. Tollefsbol, 2015

      Epigenetic Technological Applications

      Edited by Y. George Zheng, 2015

      Epigenetic Cancer Therapy

      Edited by Steven G. Gray, 2015

      DNA Methylation and Complex Human Disease

      By Michel Neidhart, 2015

      Epigenomics in Health and Disease

      Edited by Mario F. Fraga and Agustin F. Fernández, 2015

      Epigenetic Gene Expression and Regulation

      Edited by Suming Huang, Michael Litt, and C. Ann Blakey, 2015

      Epigenetic Biomarkers and Diagnostics

      Edited by Jose Luis García-Giménez, 2015

      Drug Discovery in Cancer Epigenetics

      Edited by Gerda Egger and Paola Barbara Arimondo, 2015

      Medical Epigenetics

      Edited by Trygve O. Tollefsbol, 2016

      Chromatin Signaling

      Edited by Olivier Binda and Martin Fernandez-Zapico, 2016

      Chromatin Regulation and Dynamics

      Edited by Anita Göndör, 2016

      Neuropsychiatric Disorders and Epigenetics

      Edited by Dag H. Yasui, Jacob Peedicayil and Dennis R. Grayson, 2016

      Genome Stability

      Edited by Igor Kovalchuk and Olga Kovalchuk, 2016

      Polycomb Group Proteins

      Vincenzo Pirrotta, 2017

      Epigenetics and Systems Biology

      Leonie Ringrose, 2017

      Copyright

      Academic Press is an imprint of Elsevier

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      Copyright © 2018 Elsevier Inc. All rights reserved.

      No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

      This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

      Notices

      Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

      Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

      To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

      Library of Congress Cataloging-in-Publication Data

      A catalog record for this book is available from the Library of Congress

      British Library Cataloguing-in-Publication Data

      A catalogue record for this book is available from the British Library

      ISBN: 978-0-12-809552-2

      For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

      Publisher: Mica Haley

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      Editorial Project Manager: Lisa Eppich & Barbara Makinster

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      Designer: Mark Rogers

      Typeset by TNQ Books and Journals

      List of Contributors

      Tomi Akinyemiju,     University of Alabama at Birmingham, Birmingham, AL, United States

      Samuel Anti,     Alabama State University, Montgomery, AL, United States

      Ritikraj Arya,     Loveless Academic Magnet Program High School, Montgomery, AL, United States

      Marine Baptissart

      INSERM U 1103, Génétique Reproduction et Développement (GReD), Clermont-Ferrand, France

      Université Clermont Auvergne, GReD, Clermont-Ferrand, France

      CNRS, UMR 6293, GReD, Clermont-Ferrand, France

      Raffaela Barbano,     IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

      Timothy M. Barrow,     Newcastle University, Newcastle upon Tyne, United Kingdom

      Teena Bhatla,     New York University School of Medicine, New York, NY, United States

      Kartz Bibb,     Alabama State University, Montgomery, AL, United States

      William L. Carroll,     New York University School of Medicine, New York, NY, United States

      Fabio Coppedè,     University of Pisa, Pisa, Italy

      Jovana Klajic

      Akershus University Hospital, Lørenskog, Norway

      OUS Radiumhospitalet, Oslo, Norway

      Vessela Kristensen

      Akershus University Hospital, Lørenskog, Norway

      OUS Radiumhospitalet, Oslo, Norway

      Sanjay Kumar,     Alabama State University, Montgomery, AL, United States

      Bernard Kwabi-Addo,     Howard University, Washington, DC, United States

      Angela Lopomo

      University of Pisa, Pisa, Italy

      University of Siena, Siena, Italy

      Pillai Pallavi Madhusoodhan,     Icahn School of Medicine at Mount Sinai, New York, NY, United States

      Emmanuelle Martinot

      INSERM U 1103, Génétique Reproduction et Développement (GReD), Clermont-Ferrand, France

      Université Clermont Auvergne, GReD, Clermont-Ferrand, France

      CNRS, UMR 6293, GReD, Clermont-Ferrand, France

      Shabana S. Meyering

      Northern Virginia Community College, Woodbridge, VA, United States

      Georgetown University, Washington, DC, United States

      Manoj K. Mishra,     Alabama State University, Montgomery, AL, United States

      Paola Parrella,     IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

      Barbara Pasculli,     IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

      Sabita N. Saldanha,     Alabama State University, Montgomery, AL, United States

      Brenda C. Salumbides,     Arrowhead Regional Medical Center, Colton, CA, United States

      Lauriane Sédes

      INSERM U 1103, Génétique Reproduction et Développement (GReD), Clermont-Ferrand, France

      Université Clermont Auvergne, GReD, Clermont-Ferrand, France

      CNRS, UMR 6293, GReD, Clermont-Ferrand, France

      Rajesh Singh,     Morehouse School of Medicine, Atlanta, GA, United States

      Shriti Singh,     Banaras Hindu University, Varanasi, India

      Lula Smith,     Alabama State University, Montgomery, AL, United States

      David H. Volle

      INSERM U 1103, Génétique Reproduction et Développement (GReD), Clermont-Ferrand, France

      Université Clermont Auvergne, GReD, Clermont-Ferrand, France

      CNRS, UMR 6293, GReD, Clermont-Ferrand, France

      Natalie White,     Alabama State University, Montgomery, AL, United States

      Chapter 1

      Epigenetic Dysregulation in Pediatric Leukemia

      Pillai Pallavi Madhusoodhan¹, William L. Carroll², and Teena Bhatla²     ¹Icahn School of Medicine at Mount Sinai, New York, NY, United States     ²New York University School of Medicine, New York, NY, United States

      Abstract

      Clinical and basic research in pediatric leukemia has been at the forefront of oncological advances since its inception, and results have also been successfully translated into effective therapeutics. This is reflected in the gratifying improvement in patient survival from 20% to 30% in the 1960s to greater than 90% in latest trials in the 2000s. This success is the result of the integration of multiagent chemotherapy, Central nervous system (CNS) prophylaxis, disciplined randomized clinical trials, and appropriate risk stratification based upon biological and clinical risk groups. The recognition of distinct biological subgroups characterized by whole chromosome gains or losses, and translocations refined treatment stratification. Even more recently the development of high throughput genomic analysis led to the discovery of focal copy number gains/losses, somatic mutations, and gene expression signatures that drive leukemogenesis and resistance to therapy. All of these critical advances have focused on changes in the DNA code itself but it is increasingly clear that epigenetic alterations in DNA methylation, histone modifications, and noncoding RNAs play a major role in shaping gene expression. Indeed, many of the somatic alterations occur in genes that control these processes and the advent of novel agents that target the epigenome are in clinical trials.

      Keywords

      DNA methylation; Epigenetics; Gene expression; Histone modifications; Leukemogenesis; Pediatric leukemia

      1. Introduction

      Pediatric leukemia is the most common cancer affecting children, forming up to 30% of all pediatric malignancies and spanning a wide range of clinical and biological subgroups [1]. The overwhelming majority of cases are acute leukemias which are broadly divided into lymphoid and myeloid subtypes. The acute lymphoid leukemias are further subdivided based upon cell of origin into B-cell acute lymphoblastic leukemia (B-ALL) and T-cell acute lymphoblastic leukemia (T-ALL). Acute myeloid leukemia (AML) is further divided into subgroups depending upon specific cytogenetic abnormalities and upon histopathology in the absence of cytogenetic abnormalities. Chronic myeloid leukemia (CML) in children has a low incidence of 1.3 per million, whereas chronic lymphocytic leukemia (CLL) is extremely rare with only one published case study [2]. Juvenile myelomonocytic leukemia (JMML) is another rare myeloproliferative/myelodysplastic disorder seen in pediatrics with a low incidence of 1–2 per million [1].

      Tumor karyotype, and more recently molecular analysis, played a major role in pediatric leukemia and has been utilized for risk stratification, prognosis, and treatment modifications. The well-known Philadelphia chromosome or breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1) fusion is more common in adults and relatively rare in pediatric leukemias. Cytogenetic changes are not used to stratify therapy in T-lymphoblastic leukemia (T-ALL), but the most common mutations are those causing constitutive activation of the Notch homolog 1 (NOTCH1) signaling protein or in the gene encoding F-box and WD repeat domain containing 7 (FBXW7) which is responsible for the degradation of NOTCH1 [3]. Leukemia in infants under 1  year of age, or infant leukemia, is considered a distinct entity, where 70%–80% of cases are associated with rearrangements in the mixed lineage leukemia (MLL) gene on chromosome 11, which has been described as having multiple fusion partners (over 50 have been described) [4,5]. MLL-rearranged (MLLr) leukemias are known to be particularly aggressive with a poor prognosis [4].

      The stem cell hypothesis, whereby the malignancy originates from a core group of leukemic stem cells (LSCs) or leukemia initiating cells (LICs), possessing the critical triad of self-renewal, pluripotency, and unchecked proliferation, has developed particular credibility in AML [1]. The sequence of genetic events leading to the development of AML is theorized to be a two-step process, whereby the initial or Class II lesion is one affecting transcription factors such as core binding factor (CBF), CCAAAT/enhancer binding protein alpha (CEBPα), and the MLL rearrangements, which block differentiation. The second event is a Class I lesion which is an activating mutation in signaling pathways such as internal tandem duplication of Fms-related tyrosine kinase 3 (FLT3-ITD), KIT proto-oncogene receptor tyrosine kinase (c-Kit), rat-sarcoma (Ras), leads to proliferative and self-renewal properties. Another well-known mutation in AML is the t(15;17) which gives rise to promyelocytic leukemia gene-retinoic acid receptor alpha gene (PML:RARα) fusion product, inducing a block in differentiation. The typical adult AML associated lesions of monosomy7 or monosomy or Del(5q) are less frequent in pediatric AML cases.

      Relapsed leukemia has remained a continuing clinical challenge in pediatric oncology, wherein outcomes have remained poor (overall survival 25%–40%) despite multiple therapy intensifications and hematopoietic stem cell (HSC) transplant. The key factor underlying relapse is the development of chemoresistance. In many cases the relapse clone is present at initial diagnosis as a minor population, which gains a survival advantage under the selective pressure of chemotherapy eventually becoming the dominant clone at relapse [5]. Multiple relapse-specific genetic aberrations have been shown to contribute to chemoresistance to specific agents (e.g., glucocorticoid resistance via transducin beta like 1 X-linked receptor 1 (TBL1XR1) deletions and CREB-binding protein (CREBBP) mutations, 6-mercaptopurine and 6-thioguanine resistance via 5′-nucleotidase, cytosolic II (NT5C2) and phosphoribosyl pyrophosphate synthetase 1 (PRPS1) mutations) or pan resistance to all chemotherapeutic agents (e.g., wingless-type MMTV integration site family (Wnt) and mitogen-activated protein kinase (MAPK) pathway activation).

      The study of epigenetic mechanisms in pediatric leukemia came into focus toward the end of the 1990s and the beginning of this century, amidst a wave of rising interest in gene expression, beyond classical chromosomal or nucleotide alterations. The field of epigenetics in its original form was conceived in the 1940s, as an enquiry into the development of different phenotypes during embryogenesis. In its most modern version, the term epigenetics is now understood to refer to a set of heritable changes in gene expression, which is not dependent on the alteration of actual nucleotide sequence of DNA. Instead it involves of processes which impact how the nucleotide sequence is expressed by altering an array its availability for transcription and translation. These processes include most commonly methylation of DNA, modifications of histone tails, and noncoding RNAs. The role of each of these mechanisms and their proposed and proven roles in pediatric leukemias will be discussed in the sections below.

      2. DNA Methylation

      Methylation of cytosine (C) residues in DNA has been recognized as a significant epigenetic mechanism in both normal and neoplastic cells for many years. Methylation specifically occurs on cytosine residues located next to guanosine (G) nucleotides, with the cytosine being 5′ to the guanosine. The enzymes responsible for the transfer of the methyl groups are known as DNA methyltransferases (Dnmt), of which Dnmt1 is responsible for replicating existing methylation patterns (maintenance methylation), whereas Dnmt3a and Dnmt3b are considered responsible for de novo methylation [6]. In the genome, C and G may occur next to each other as isolated dinucleotides (CpG sites) or in clusters about 1  kb in length, which are also known as CpG "islands." The CpG islands are most commonly found to be positioned near gene promoter regions. Methylation of the cytosine residue on these islands was observed to cause silencing of the genes downstream of the promoter. Thus, it was conceivable quite early on, that interplay of methylation and the location of these CpG islands may have a significant role in gene expression in neoplasia. In normal cells, DNA methylation is most commonly utilized as a silencing mechanism for large swathes of the genome which do not need to be actively transcribed. Thus about 70%–80% of CpG sites in the genome are maintained in a methylated state [7]. In contrast, the large majority of CpG islands are relatively unmethylated, except in specific situations such as silencing of one of the two X chromosomes in females and during genomic imprinting [8].

      2.1. Role of DNA Methylation in Hematopoiesis

      Within the hematopoietic system, methylation has been found to be crucial in differentiation, lineage commitment, and self-renewal. In an in vitro study of adult female HSCs and also more mature differentiated hematopoietic cells, it was found that DNA methylation was responsible for fine tuning lineage specificity as the stem cell evolves and differentiates [9]. HSCs and progenitors tend to be more hypomethylated, while mature cells such as B-cells and neutrophils demonstrated progressively increasing methylation, with silencing of genes representing alternative lineages. In an in vivo model of adult murine HSCs DNA methylation was found to be predictive of cell type, lineage, and differentiation state [10]. Lymphoid progenitors tend to be twice as methylated as myeloid progenitors, possibly suggesting a greater role for methylation in lymphoid development than in myeloid [10,11]. Loss of the maintenance methyltransferase Dnmt1 leads to significant impairment of the ability of HSCs to self-renew and also loss of bone marrow niche retention, in addition to disrupting differentiation [12], whereas disruption of the de novo methyltransferases Dnmt3a and Dnmt3b in mice HSCs led to failure of self-renewal, but not differentiation [13]. These observations indicate a profound role for DNA methylation in normal hematopoietic development.

      2.2. Role in Leukemogenesis

      Relative to normal hematopoietic cells, leukemic cells have been repeatedly found to express a markedly different epigenetic signature, dominated by a pattern of promoter hypermethylation [14]. Broske et al. chose to examine the role of Dnmt1 in LSCs, in addition to normal HSCs [15]. In this report, myelocytomatosis oncogene-B-cell CLL/lymphoma 2(Myc-Bcl2) was coexpressed in Dnmt1 deficient cells which were then transplanted into sublethally irradiated mice. Mice transplanted with Myc-Bcl2/Dnmt1−/− cells showed significant latency in development of leukemia as compared to mice who had been transplanted with Myc-Bcl2/Dnmt1+/+ [15]. Hypomethylation was also seen to markedly reduce proliferation of MLL-AF9 (mixed lineage leukemia-ALL1-fused gene from chromosome 9 protein) transduced LSCs, suggesting that constitutive methylation is crucial to the self-renewal property of LSCs.

      In a comparison of combined methylation and gene expression profiles, Chatterton and colleagues found a prominent difference between B-ALL cells as compared to non-leukemic controls, which included samples taken from patients in remission and from unaffected patients [14]. A total of 325 genes were found to be hypermethylated and downregulated whereas 45 genes were hypomethylated and upregulated across all subtypes of B-ALL [14]. Some of the genes which were downregulated included those affecting cytokines such as interleukin 7 (IL7); kinases such as Erb-B2 receptor tyrosine kinase 4 (ERBB4); and critical transcription factors such as GATA-binding factor 4(GATA4) and homeobox (Hox) genes. The affected genes covered a wide spectrum of functionality from cell signaling such as the cyclic adenosine monophosphate (cAMP) signaling pathway, cation transport including calcium and potassium channels, to apoptosis and proliferation. B-lymphoblasts utilize the cAMP signaling pathway as a mechanism of apoptosis and disruptions in this pathway could be utilized by leukemic cells as a protective mechanism against apoptosis. Similarly, dysfunction in cation transport channels could also impact apoptotic mechanisms. Genes such as proapoptotic WT1 regulator (PAWR) and ERBB4, which have roles in apoptosis induction, were found to be hypermethylated and repressed. Significant changes in genes from the Wnt/β-catenin pathway were noted with upregulation of Wnt family member 5B (WNT5b) and WNT1 inducible signaling pathway protein 1 (WISP1), while genes inhibiting the pathway such as the SRY (sex determining region Y)-box (SOX) group were downregulated. In addition to these core common epigenetic abnormalities, they also found subtype specific abnormalities, especially in the ETV6-RUNX1 group, where there was hypomethylation of Erythropoetin receptor (EPOR) which activates the Janus kinase 2-signal transducer and activator of transcription 5 (JAK2-STAT5) pathway and hypermethylation of asparginase synthetase (ASNS) gene, which can cause increased sensitivity to L-asparginase. In the hyperdiploid subgroup, there was promoter hypermethylation and downregulation of tumor suppressor genes fragile histidine triad (FHIT) and protein tyrosine phosphatase, receptor type G (PTPRG). In an integrated genomic analysis, including DNA methylation, gene expression profiling and copy number analysis, of samples from 137 children with B-ALL and 30 with T-ALL, Figueroa and colleagues showed that methylation profiles tend to cluster according to cytogenetic subtype and correlate strongly with specific gene expression signatures [16]. But underlying all this, there were again a set of 75 differentially methylated regions which were shared across all leukemia subtypes. Out of the 75, 66 were hypermethylated and 9 were hypomethylated. Genes affected by these common aberrations again included those involved in cell signaling, proliferation, and transcription factors.

      In AML, aberrancy in epigenetic modifiers has been found to occur with a higher frequency in older patients than in children, as demonstrated by the studies discussed below. Dnmt3a, the de novo methyltransferase, has been found to be mutated in up to 12%–22% of adult AML and to be associated with a poor outcome [17]. The mutations in Dnmt3a are broadly categorized as recurrent mutations in R882 and the all other mutations anywhere else in the gene. The Children’s Oncology Group (COG, the single largest cooperative study group in pediatric oncology in the United States) examined 180 diagnostic samples from children with AML and none were found to have Dnmt3a mutations [18]. In a study from Germany, which focused on the most commonly mutated codon, R882, of the Dnmt3a gene, mutations were found in 2 out of 195 patient samples (1%) [19]. Both these patients were older compared to the median patient age (15.45 vs. 8.56  years), in keeping with the theory that the incidence of these mutations increases with age. Other studies have also found Dnmt3a mutations in 1.2%–2.1% of pediatric AML samples [20,21]. Ten-eleven translocation (TET) family proteins regulate DNA methylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC), which is then degraded down to unmodified cytosine via multiple intermediate steps. Mutations in TET2 (TET methylcytosine dioxygenase 2 gene) have been detected in multiple hematological malignancies, giving rise to the hypothesis that disruption of TET2-mediated DNA demethylation has a crucial role to play in the development of these malignancies [22]. Inactivating TET2 mutations are detected in 7%–23% of adult AML, but reports of such mutations in pediatrics are very rare ranging from 1.7% to 3.8% [21,23,24]. The prognostic impact of TET2 mutations in adults has been controversial, but most studies report an association with poor prognosis [25]. Though the number of pediatric patients with somatic mutations in TET2 has been too low to achieve meaningful outcome data, Kutny et al. showed in their study from the COG that a specific SNP of TET2 RS2454206 was associated with improved survival in two separate clinical trials in their patient cohort [23]. This was associated with lower non-relapse mortality than disease relapse itself.

      Isocitrate dehydrogenase enzymes 1 and 2 (IDH1, IDH2) are responsible for the conversion of isocitrate to alpha ketoglutarate and if mutated, cause accumulation of an oncometabolite alpha hydroglutarate (2HG) which inhibits TET2 and thus causes hypermethylation. IDH1/2 mutations are seen in 15%–33% of adult AMLs and only in 1%–3.5% of pediatric AMLs [21,26]. TET2 and IDH mutations are generally found to be mutually exclusive, supporting a unified theory of their mechanisms of action. The actual methylome of AML in adults has been well studied and similar studies in pediatrics are underway. In an examination of 344 adult patient samples (median age 48  years), it was shown that 16 distinct types of AMLs were identified based upon methylation signature [27]. Most of them coincided with the cytogenetic subtype, but five new distinct groups independent of cytogenetic subtype were identified. Distinct subgroups within existing cytogenetic groups were also identified. For example, the nucleophosmin (NPM)-mutated AML clustered in four distinct methylation profiles and CCAAT/enhancer binding protein alpha (CEBPA)-mutated AML showed two varied methylation profiles, one hypermethylated and one hypomethylated. Fms-related tyrosine kinase 3 (FLT3)-mutated AML did not show any distinct hypermethylation patterns, suggesting that its pathogenesis does not involve epigenetic modification. Similar to the observations in ALL studies, there was a set of 45 dysregulated genes identified, which were common across at least 10 of the 16 AML subtypes and present in up to 70% of the cases. Most of these genes were hypermethylated and silenced or downregulated. They included tumor suppressors such as PDZ domain-containing protein 2 (PDZD2), which is involved in intracellular signaling and transcriptional regulators such as zinc finger protein 667 (ZNF667) and 582 (ZNF582), protein inhibitor of activated STAT 2 (PIAS2), and cyclin-dependent kinase 8 (CDK8). The group also identified a 15 gene-based methylation classifier which was able to predict patient outcomes based upon methylation patterns. One of the first detailed studies of the methylation profiles and gene expression profiles in pediatric AML was recently presented as an abstract [28]. In this study of methylations profiles of 175 pediatric patients with AML and gene expression profiles of 166 patients, Pounds et al. found a very strong correlation between methylation and gene expression [28]. They also found that methylation profiles were distinct based upon risk groups, with lower risk groups being more hypomethylated. The methylation profiles were also found to have clinical correlation in terms of chemo sensitivity, disease response, and event-free survival [28].

      Epigenetic mechanisms are known to play a major role in MLL-rearranged (MLLr) infant leukemia. The methylation patterns in MLLr leukemias were also found to be strikingly different and clustering separately from MLL wild-type infant leukemias or B-ALL [29,30]. They demonstrate a pattern of hypermethylation in both promoter and non-promoter regions [29]. Hypermethylation was found to be more prominent in patients with the t(4;11) and t(11;19) translocations, in whom it was also found to be associated with a higher risk of relapse [31]. Gene expression profiles demonstrated increased expression of FLT3, homeobox A9 (HoxA9), and myeloid ecotropic viral integration site 1 homolog (MEIS1) with suppression of key genes such as death-associated protein kinase 1 (DAPK1), Harakiri (HRK), FHIT, and C–C motif chemokine receptor 6 (CCR6). DAPK1 and HRK are both associated with initiation and induction of apoptosis, whereas CCR6 is a receptor for chemokine CL20. Both gene expression profiles and methylation patterns were found to be reversible upon treatment with demethylating agents [30,31].

      Relapsed leukemias have been shown to have methylation patterns which differ from their diagnosis samples. Genome-wide methylation profiling of 33 matched diagnosis-relapse samples showed marked hypermethylation of the chemoresistant relapsed samples as compared to the corresponding diagnosis ones [32]. It was found that 1147 CpG sites, which correspond to 905 genes, were hypermethylated at relapse and 81 CpG sites (corresponding to 79 genes) were hypomethylated. Correlation of the methylation profiles of these 984 differentially methylated genes with gene expression, 251 genes with promoter hypermethylation showed downregulation of expression, and 29 genes whose promoters were hypomethylated demonstrated increased expression [32]. This suggests that DNA methylation has an active role in gene expression in relapsed leukemia. The wingless-type MMTV integration site family (Wnt) pathway has been implicated in broad pan chemoresistance in relapsed leukemia and in this study; they found the hypermethylation and downregulation of many Wnt pathway regulators in relapsed primary patient samples. In addition, they noted downregulation of inhibitors of the β-catenin/TCF/LEF complex, including adenomatosis polyposis coli tumor suppressor (APC), Wilm’s tumor 1 (WT1), and members of the cadherin and SOX families of genes. In a collaborative study between the COG and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project, high resolution, genome-wide methylation profiling was performed on a total of 178 patient samples (110 diagnosis, 68 relapse) from 111 pediatric patients with B-ALL [33]. Comparison of 67 paired diagnosis-relapse samples showed marked aberration involving 888 genes, with 70% of them being hypermethylated at relapse with most of the hypermethylation being seen in promoter regions [33]. They were also able to observe distinct methylation signatures identifying specific cytogenetic subgroups. In addition, there were 1686 genes which were differentially methylated in all the leukemic samples (irrespective of subtype) as compared to normal B-cell samples.

      In conclusion, multiple studies have provided abundant evidence to suggest that DNA methylation, in particular promoter hypermethylation, has an important role to play in pediatric leukemia, across all subtypes. On a fundamental level, the finding that distinct cytogenetic subgroups have distinct methylation profiles suggests that methylation plays a role in dictating specific phenotypes. But there also seem to be some core common changes in methylation shared by leukemic cells, which are not seen in normal cells. Thus, methylation appears to contribute to both basic leukemogenic changes and to controlling the clinical behavior associated with cytogenetic aberrations. A majority of the changes in methylation controlled expression center around genes involved in cell signaling, proliferation, differentiation, and apoptosis. From a clinical perspective, methylation has been shown to be useful in predicting chances of relapse and outcomes. Drugs which reverse methylation patterns such as decitabine have been shown to reverse the methylation and gene expression changes, providing an exciting new therapeutic option, especially in relapsed leukemia [34].

      3. Histone Modification

      Histones are a family of proteins, which organize the spatial layout of DNA. DNA is wrapped around groups of histones to form structures called nucleosomes. Of the five families of proteins that form histones, H2A, H2B, H3, and H4 are the core histones, whereas H1/H5 are the linker histones [35]. Posttranslational modifications of histones have great impact on gene expression by changing the organization of DNA and its accessibility for binding modulators of transcription. Histone modification can be controlled by acetylation or methylation of specific amino acids within the N-terminal tails of the histones, and the impact of each modification is very specific. For example, trimethylation of the lysine residue in position 4 of histone H3 (H3K4me3) causes loosening of chromatin configuration and thus leads to increased transcription, hence this is considered an activating mark. Similarly, acetylation of the lysine at position 9 of H3 (H3K9AC) and demethylation of the lysine at position 79 of H3 (H3K79me2) are also activating marks, whereas trimethylation of lysine at position 9 of H3 (H3K9me3) and trimethylation of lysine at position 27 of H3 (H3K27me3) are repressive marks since they cause condensation of chromatin and decreased accessibility. Modifiers of the histone code are typically described as writers, readers, or erasers [36]. Writers are enzymes such as histone acetyl transferases (HATs) or histone methyltransferases (HMTs) which add acetyl or methyl groups to histone tails and create epigenetic marks. These marks are then recognized by reader proteins such as bromodomain, chromodomains, or PHD fingers. Histone deacetylases (HDACs) and histone demethylases (HDMs) function as epigenetic erasers, which are used to delete or remove these marks. The integrity of epigenetic modulation is maintained by a tight balance between these various enzymes and their interactions.

      3.1. Role in Hematopoiesis

      Hematopoiesis is a complex process involving a strict hierarchy whereby multiple lineages are all generated from a common precursor, the HSC. This requires tight control of gene expression in an appropriate chronological and sequential order. Epigenetic mechanisms provide the perfect tool for such control.

      Histone methyltransferases (HMTs) transfer methyl groups from the donor S-adenosylmethionine (SAM) to lysine or arginine residues on histone tails. SET (suppressor of variegation, enhancer of zeste, and trithorax proteins) domains are specific catalytic domains associated with methyltransferase activity. HMTs are divided into three groups based on their SET domains, with the first group being SET-domain containing lysine-specific HKMTs, the second being non-SET containing lysine HKMTs, and the third being arginine-specific HMTs, also known as protein arginine methyltransferases or PRMTs [37]. HMTs of particular interest in hematopoiesis include the nuclear receptor binding SET domain protein (NSD) family of SET domains, which consists of NSD1, NSD2 (also known as multiple myeloma SET domain containing protein or MMSET), and NSD3. NSD2/MMSET is responsible for methylation of the lysine at H36 or H3K36me2, which is an activating mark [38]. Overexpression of MMSET has been shown to cause increase in H3K36 methylation with a concomitant decrease in methylation of lysine at position 27 of H3 (H3K27), leading to a more open chromatin structure [39]. Loss of MMSET led to a decrease in cell growth and increased apoptosis, suggesting that MMSET has influence over crucial genes involved in cell growth and death [39]. PRMTs have been shown to have a role in myeloid differentiation, via methylation of H4 arginine 3 (H4R3), which causes increased retinoic acid (RA)-mediated gene transcription [40]. HMTs are also involved in the regulation of expression of one of the crucial gene sets involved in control of hematopoiesis, namely the homeobox (Hox) groups of genes [41]. Hox genes are homeo-domain containing transcription factors, which consist of 39 genes, grouped into four distinct clusters, namely Hox A, Hox B, Hox C, and Hox D. They are expressed in HSCs and progenitors, and have stage and differentiation-associated restriction in expression [42]. For example, Hox A genes are expressed in myeloid cells, Hox B in erythroid cells, and Hox C in lymphoid cells. In a similar fashion, depending on stage of differentiation, HoxB3, HoxB4, HoxA9 are expressed in undifferentiated cells whereas committed myeloid cells show HoxA10 and HoxB8 expressions [41]. Hox gene overexpression or oncogenic fusions has been shown to have a strong role in leukemogenesis and comes under the group of Class II mutations in AML, which block differentiation [41,42]. The epigenetic control of Hox genes mediates the polycomb group (PcG) or trithorax group (Trx) of proteins. The PcG group has two major repressive complexes known as polycomb repressive complex 1 (PRC1) and polycomb repressive complex 2 (PRC2). PRC2 consists of four subunits enhancer of zeste 1/1 (EZH1/2), embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12) and retinoblastoma-binding protein P48 (RBAP48). EZH2 is the methyltransferase responsible for the di- and trimethylation of H3K27, which, as discussed earlier, is a repressive mark. The PRC1 complex recognizes the H3K27me3 mark via its chromobox (CBX) group and further causes gene suppression through ubiquination of histone H2A and recruitment of DNA methyltransferases. PRC proteins are assisted in chromatin binding and DNA sequence–specific binding by intermediary proteins such as addition of sex combs like 1 (ASXL1). Mutations in PRC components EZH2, SUZ12, and EED are often seen in leukemia, especially T-cell leukemias [43].

      Histone demethylases are a relatively less understood group of proteins, with two major subgroups being the lysine-specific demethylase (LSD1) group and the jumonji C (JmjC). LSD1 removes the methyl groups from lysine residues at positions 4 and 9 on H3 (H3K4/H3K9). It also forms part of a larger repressive complex involving corepressor of repressor element-1 silencing transcription factor (CoREST) and histone deacetylase 2 (HDAC2). Kerenyi and colleagues, in an integrated genomic analysis combining global occupancy of LSD1, mono- and dimethylation of its substrate H3K4, and gene expression profiling, found that LSD1 suppressed expression of HSC and progenitor cell genes and promoted differentiation and maturation [44]. This was in keeping with studies in a mouse model where knockdown of LSD1 causes expansion of the progenitor cell compartment, but marked decrease in development of mature erythrocytes, granulocytes, and platelets [45]. Loss of lysine-specific demethylase 5B (JARID1B), a member of the jumonji (Jmj) family of demethylases, has also been shown to impact HSC self-renewal [46].

      HATs are a group of enzymes which acetylate specific lysine residues on histones and also multiple nonhistone targets, such as p53 and c-Myc, by transferring an acetyl group from acetyl-CoA [47]. Acetylation of histones causes loosening of chromatin structure and increases transcription. HATs are classified into two basic groups, based upon cellular localization, with Type A HATs being located in the nucleus and Type B HATs being located in the cytoplasm [47]. Type A HATs are further divided into five families including the GNAT (GCN5-related acetyltransferases) groups: GCN5 (General Control Nonderepressible) family, PCAF (p300/CBP associated factor) family, ELP3 (Elongator complex protein 3) family, and then the CBP/p300 family and the MYST family (includes MOZ, MOF et al.). Type B HATs acetylate newly formed histones and its members are less well defined but include histone acetylase 1 (HAT1). HATs have been shown to have a crucial role in hematopoiesis and in HSCs and progenitors by supporting differentiation, promoting self-renewal, controlling proliferation, and regulating apoptosis [47]. In a mouse model, loss of CREB-binding protein (CBP) was found to profoundly impact HSC self-renewal but not differentiation whereas lack of p300 caused a block in differentiation, but loss of either p300 or CBP could lead to tumorigenesis [48]. Thus, both HATs were essential for maintenance of normal HSCs and had distinct functions, which were both equally important in preventing the rise of malignancy. Similarly, mutations in another HAT, the Monocytic leukemia zinc finger protein (MOZ), a member of the MYST family, was found to cause embryonic lethality in mice when homozygous MOZ mutated HSCs were found to be incapable of contributing to hematopoiesis [49]. In addition to their role in HSCs HATS have also been found to be important in lymphoid and myeloid progenitors and their development. All hematopoietic developments require c-Myb-mediated transcriptional control and the KIX domains in p300 and CBP are responsible for interacting with and regulating c-Myb-related activity. Mutations in the KIX regions of CBP, and more importantly p300, led to gross abnormalities in hematopoiesis across multiple lineages [48]. The forkhead box P3 (Foxp3) protein, which controls development of the Treg suppressor phenotype, is maintained in an acetylated state by p300, which prevents its degradation. Tregs normally maintain immune homeostasis and prevent autoimmunity, but it has been postulated that their downregulation can help increase antitumor activity. Inhibition or deletion of p300 has been shown to increase apoptosis in Foxp3+ Treg cells and also limit tumor growth in immunocompetent but not immunocompromised mice [50].

      In opposition to HATs are the histone deacetylases or HDACs, which cause condensation of chromatin and transcriptional repression. They are classified into four groups, Class I, IIa, IIb, and IV, of which Class I are known to be the ones expressed in most cells types with a significant role in cell growth and differentiation. Specifically within the hematopoietic system, HDACs are found to have limited role in HSCs but progressively increase in function as differentiation progresses, which suggests they have a major role in lineage assignment and development [51]. Inhibition of HDACs has been found to decrease differentiation and induce expansion of HSCs ex vivo [52].

      Epigenetic dysregulation plays a crucial role in certain cytogenetic subtypes of leukemia, e.g., MLL-rearranged leukemias and PML-RARα fusion in acute promyelocytic leukemia (APML). The wild-type MLL protein complex has a positive effect on Hox gene expression, and complete lack of MLL has been shown to cause embryonic lethality [53–56]. The MLL proteins contain a SET domain which has been shown to cause methylation of H3K4, which is an activating mark [55,57]. MLL has also been demonstrated to directly bind promoters of Hox genes [57]. It seems to have the ability to directly bind CBP and also form complexes with the HAT MOF, all of which contribute to its ability to cause active transcription [58,59]. MLL heterozygous mice showed decreased HSC pool, abnormalities in hematopoiesis along with decreased expression of Hoxc-9 [53,54]. MLL has been proven to be crucial in hematopoietic development, where in a chimeric animal model, the MLL-deficient cells failed to generate any mature myeloid or lymphoid cells, and even fetal or embryonic HSCs pools failed to develop in the absence of a critical minimum level of MLL [60].

      The PML-RARα fusion in APML is a cytogenetic abnormality that is a prime example of epigenetically mediated differentiation block and leukemogenesis [37]. During normal hematopoiesis, the RARα receptor functions as a regulator of normal myelopoesis, which is dependent on binding of its ligands, all-trans RA or 9-cis RA [61]. In the absence of any ligands, RAR forms a heterodimer with RXR (retinoid X receptors) which then binds to corepressor complexes such as nuclear receptor corepressor 1 (NCOR). The corepressor complexes further recruit HDACs which cause a closed

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