Genetic and Epigenetic Characterization of Pediatric High Hyperdiploid Acute Lymphoblastic Leukemia
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Genetic and epigenetic characterization of pediatric high hyperdiploid acute lymphoblastic leukemia Davidsson, Josef 2009 Link to publication Citation for published version (APA): Davidsson, J. (2009). Genetic and epigenetic characterization of pediatric high hyperdiploid acute lymphoblastic leukemia. Lund University: Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 GENETIC AND EPIGENETIC CHARACTERIZATION OF PEDIATRIC HIGH HYPERDIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA Akademisk Avhandling av JOSEF DAVIDSSON Blekingska Nationen som med vederbörligt tillstånd av Medicinska Fakulteten vid Lunds universitet för avläggande av doktorsexamen i medicinsk vetenskap kommer att offentligen försvaras i föreläsningssal F1, centralblocket, Universitetssjukhuset i Lund, fredagen den 27 november 2009 kl 10.00 Fakultetsopponent: Dr Lyndal Kearney Section of Haemato-Oncology The Institute of Cancer Research, University of London Sutton, UK GENETIC AND EPIGENETIC CHARACTERIZATION OF PEDIATRIC HIGH HYPERDIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA JOSEF DAVIDSSON DEPARTMENT OF CLINICAL GENETICS FACULTY OF MEDICINE LUND UNIVERSITY 2009 This thesis is dedicated to my mother and father, for always believing in me. What is it that we human beings ultimately depend on? We depend on our words. We are suspended in language. Our task is to communicate experience and ideas to others. Niels Bohr © Josef Davidsson ISSN 1652-8220 ISBN 978-91-86443-01-6 Printed in Sweden by Media Tryck AB, Lund 2009 TABLE OF CONTENTS ABBREVIATIONS 7 ORIGINAL ARTICLES 8 PREFACE 9 INTRODUCTION 10 Hematologic malignancies 10 Genetic aberrations in ALL 11 Epigenetic changes in ALL 16 REVIEW OF PEDIATRIC HeH ALL 19 Cytogenetic features 19 Mutations 21 Epigenetic changes 22 Clinical features 23 Incidence 24 Etiology 25 Origin of HeH 27 Leukemogenesis 28 Gene dosage 29 Relapse 29 THE PRESENT STUDY 32 Aims 32 Patients and samples 33 Methods 35 Results 41 Discussion 47 Conclusions 54 SUMMARY IN SWEDISH 58 ACKNOWLEDGEMENTS 61 REFERENCES 63 ABBREVIATIONS ALL acute lymphoblastic leukemia AML acute myeloid leukemia BAC bacterial artificial chromosome BASE bioarray software environment BL Burkitt lymphoma CGH comparative genomic hybridization CML chronic myeloid leukemia COG Children’s Oncology Group FISH fluorescent in situ hybridization GWA genome-wide association HeH high hyperdiploid MeDIP methylated DNA immunoprecipitation NOPHO Nordic Society of Paediatric Haematology and Oncology PCR polymerase chain reaction Ph Philadelphia chromosome RT reverse transcriptase SNP single nucleotide polymorphism UPD uniparental isodisomy WBC white blood cell 7 ORIGINAL ARTICLES This thesis is based on the following articles, which will be referred to in the text by their Roman numerals as listed below. I. Davidsson J, Andersson A, Paulsson K, Heidenblad M, Isaksson M, Borg Å, Heldrup J, Behrendtz M, Panagopoulos I, Fioretos T and Johansson B (2007). Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3. Hum Mol Genet 16: 2215-2225. II. Davidsson J, Lilljebjörn H, Andersson A, Veerla S, Heldrup J, Behrendtz M, Fioretos T and Johansson B (2009). The DNA methylome of pediatric acute lymphoblastic leukemia. Hum Mol Genet 18: 4054-4065. III. Davidsson J, Paulsson K, Lindgren D, Lilljebjörn H, Chaplin T, Forestier E, Andersen MK, Nordgren A, Rosenquist R, Fioretos T, Young BD and Johansson B (2009). Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK- RAS mutations. Submitted. Article I and II are reproduced with kind permission from Oxford University Press. 8 PREFACE The treatment of childhood acute lymphoblastic leukemia (ALL) is one of the true success stories of modern medicine. Before 1950, childhood leukemia was uniformly fatal, usually within a period of 3 months. Death from hemorrhages and severe infections was routine and the only treatment available, blood transfusions, offered little help. However, during the 1950’s, treatment radically changed with the introduction of drugs like methotrexate, 6- mercaptopurine and cortisone; chemotherapy had been born. Since 1975, the refinements of existing protocols have resulted in a survival rate of nearly 80%. Although this is remarkable, many problems linger. Except for Imatinib, used to treat Philadelphia chromosome (Ph) positive ALL, no new major therapeutic breakthrough has been made during the last 30 years and therapy still remains complex, expensive and very toxic to the patient. In addition, the disease etiology is unknown and there is thus no way of preventing ALL. The topic of this thesis is the most common form of pediatric ALL, namely high hyperdiploid (HeH) ALL, a malignancy with a favorable outcome, but unknown pathogenesis. The thesis is divided in four sections; the first introducing hematologic malignancies. In the second, section a review of pediatric HeH ALL is given. The third comprises the aims of the thesis, the material and methods used, results and a discussion, as well as the conclusions drawn. The final section includes the articles upon which the thesis is based. Lund, October 2009 9 INTRODUCTION Hematologic malignancies Hematologic malignancies comprise all the clinically, morphologically and immunophenotypically heterogeneous neoplastic disorders of the bone marrow, involving both the myeloid and lymphoid lineages of the hematopoietic system. Acute proliferative disorders, known as either acute myeloid leukemia (AML) or ALL depending on their lineage, are characterized by an accumulation of malignant immature white blood cells (blasts) in the bone marrow and, in most cases, also the peripheral blood. This causes dysfunction of the normal hematopoiesis resulting in anemia, leukocytopenia and thrombocytopenia and leading to infection and excessive bleeding in the patient (Jandl, 1996). Leukemia is a malignant disorder with a clonal origin from one single hematopoietic progenitor cell that has acquired somatic genetic changes causing neoplastic transformation. At present, the diagnosis and prognosis of the acute leukemias are based on the white blood cell (WBC) count, age of the patient, immunophenotype and morphology of the blasts and the presence of specific genetic abnormalities in the neoplastic cells (Pui and Evans, 2006). According to the Association of the Nordic Cancer Registries approximately 1000 cases of acute leukemia occur in the Nordic countries each year (http://www.ancr.nu). 10 AML predominates in adults, whereas ALL primarily is a pediatric disease (Jandl, 1996). With a characteristic age peak around 2-5 years (Pui et al., 2008) and an incidence of 5 cases per 100 000 and year in the Nordic countries (Hjalgrim et al., 2003a), ALL constitutes the most common childhood malignancy. Therefore, both when investigating pathogenesis as a scientist and when managing the leukemia in the clinic as a practitioner, ALL primarily pose a pediatric challenge. Moreover, this special setting as a childhood disease is important to keep in mind also when investigating the genetic and epigenetic origin of ALL, which is the topic of the present thesis. Genetic aberrations in ALL Acquired genetic aberrations have, during the last decades, been catalogued and associated with so many tumor types that they now count by the thousands (Mitelman et al., 2009). In some sense, it could be argued that “the riddle of cancer” to a large extent is solved. The evidence that neoplasia essentially is a genetic disease caused by a dysregulation of cellular systems due to somatic mutations in one or many founder cells is now overwhelming (Hanahan and Weinberg, 2000). This knowledge has had a major impact on the clinical management of patients with ALL and has played a significant role in helping us understand the biology underlying leukemogenesis. Historically, and also at present, the most characteristic cytogenetic feature of hematologic malignancies has been balanced chromosome translocations (Figure 1A) (Rowley, 2008). Two main functional consequences are associated with chromosome translocations. First, a balanced rearrangement can place a gene’s coding sequences under the transcriptional control of a regulatory element in close vicinity of the other 11 breakpoint, causing overexpression of the sequence from the first mentioned gene.