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Brian BW.Indd UNRAVELING MLL-REARRANGED PEDIATRIC ACUTE MYELOID LEUKEMIA BBrianrian BBW.inddW.indd 1 331-03-111-03-11 116:596:59 Unraveling MLL-rearranged Pediatric Acute Myeloid Leukemia © 2011 Brian V. Balgobind, Capelle aan den IJssel, Th e Netherlands ISBN 978-94-6169-051-7 Cover Design: Brian Balgobind Photo’s cover and chapters: www.f1-site.com Layout: Optima Grafi sche Communicatie, Rotterdam Printing: Optima Grafi sche Communicatie, Rotterdam Financial support for the print and reproduction of this thesis from the Pediatric Oncol- ogy Foundation Rotterdam (KOCR), Genzyme, Novartis Oncology and MRC Holland, is gratefully acknowledged. To perform the studies described in this thesis, B.V. Balgobind was fi nancially supported by the ‘Netherlands Organization for Scientifi c Research’ (NWO) and Pediatric Oncol- ogy Foundation Rotterdam (KOCR). No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission from the author or, when appropriate, from the publishers of the publications. BBrianrian BBW.inddW.indd 2 331-03-111-03-11 116:596:59 UNRAVELING MLL-REARRANGED PEDIATRIC ACUTE MYELOID LEUKEMIA Het ontrafelen van acute myeloïde leukemie met een MLL-gen herschikking in kinderen Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit te Rotterdam op gezag van de rector magnifi cus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden woensdag 25 mei 2011 om 09.30 uur door Brian Vinod Balgobind geboren te Delfzijl BBrianrian BBW.inddW.indd 3 331-03-111-03-11 116:596:59 PROMOTIECOMMISSIE Promotor: Prof.dr. R. Pieters Overige Leden: Prof.dr. H.R. Delwel Dr. J.P.P. Meijerink Prof.dr. C.P. Verrijzer Copromotoren: Dr. M.M. van den Heuvel-Eibrink Dr. C.M. Zwaan BBrianrian BBW.inddW.indd 4 331-03-111-03-11 116:596:59 Chapter 1 General Introduction 7 PART ONE: Chapter 2 Th e genetic heterogeneity of pediatric acute myeloid leukemia 21 Chapter 3 Identifi cation of gene expression signatures accurately predicting 45 cytogenetic subtypes in pediatric acute myeloid leukemia Chapter 4 EVI1 overexpression in distinct subtypes of pediatric acute myeloid 69 leukemia PART TWO: Chapter 5 Th e heterogeneity of MLL-rearranged acute myeloid leukemia 91 Chapter 6 Novel prognostic subgroups in childhood 11q23/MLL-rearranged 115 acute myeloid leukemia: results of an international retrospective study Chapter 7 NRIP3: A novel translocation partner of MLL detected in a pediatric 133 AML with complex chromosome 11 rearrangements Chapter 8 Leukemia-associated NF1 inactivation in patients with pediatric 139 T-ALL and AML lacking evidence for neurofi bromatosis Chapter 9 High BRE expression in pediatric MLL-rearranged AML is associated 155 with favorable outcome Chapter 10 Low frequency of MLL-Partial Tandem Duplications in pediatric acute 175 myeloid leukemia using MLPA as a novel DNA screenings technique SUMMARY AND DISCUSSION: Chapter 11 Summary 195 Chapter 12 Discussion and future perspectives 201 Chapter 13 Nederlandse samenvatting 221 ABOUT THE AUTHOR Curriculum vitae 229 List of publications 231 Dankwoord 235 PhD Portfolio 239 Abbreviations 241 APPENDIX A Supplementary data 247 APPENDIX B Color fi gures 289 BBrianrian BBW.inddW.indd 5 331-03-111-03-11 116:596:59 BBrianrian BBW.inddW.indd 6 331-03-111-03-11 116:596:59 Ch apter 1 General Introduction BBrianrian BBW.inddW.indd 7 331-03-111-03-11 116:596:59 8 Chapter 1 HEMATOPOIESIS AND LEUKEMIA Blood cells are derived from hematopoietic stem cells (HSC) that reside in the bone marrow. HSC’s are multipotent and have the capacity to diff erentiate into the cells of all blood lineages, i.e. erythrocytes, platelets, neutrophils, eosinophils, basophils, mono- cytes, T and B lymphocytes, natural killer cells, and dendritic cells (Figure 1). Leukemia is cancer of the blood in which the normal population of blood cells in the bone marrow is replaced by immature blood cells (blasts). Th ese immature cells occur due to an imbalance in diff erentiation and proliferation. Accumulation of these malignant cells in the bone marrow results in decrease of normal mature blood cells, like white blood and red blood cells and platelets. Figure 1: Th e development of diff erent blood cells from haematopoietic stem cell to mature cells ACUTE MYELOID LEUKEMIA Leukemias can be divided in several groups. Acute leukemias are characterized by the rapid increase of blast cells in the bone marrow, whereas the hallmark of chronic leukemias is the presence of mature but abnormal blood cells. A further subdivision can be made depend- ing on which cell type is aff ected. Lymphoblastic leukemias are derived from the lymphoid lineage, whereas in myeloid leukemias are derived from the myeloid lineage. In children, acute leukemias are the most frequent type of cancer1. In the Netherlands every year around 140 new children are diagnosed with leukemia of which 80% have acute lymphoblastic leukemia (ALL), whereas only 15% present with acute myeloid leukemia (AML). Th e incidence of AML increases with age and in adults it accounts for 80% of the acute leukemias with a median age of approximately 65 years2. BBrianrian BBW.inddW.indd 8 331-03-111-03-11 116:596:59 General Introduction 9 AML is a heterogeneous disease refl ected by diff erences in morphologic subtype, im- munophenotype, cytogenetic and molecular abnormalities. In the past, AML was mainly classifi ed on morphology according to the French-American-British (FAB) system into 8 categories, i.e. M0 to M7, based on the type of cell from which the leukemia developed and its degree of maturity3. More recently, the World Health Organization (WHO) introduced a classifi cation which attempts to be more clinically useful and includes morphology, im- munophenotype, genetics, and clinical features (Table 1)4. OUTCOME AND TREATMENT OF PEDIATRIC AML Over the last decades outcome in pediatric AML has improved from only 5% up to 60% with the most recent treatment protocols (Table 2)5-11. Th is has been achieved by improved chemotherapy schedules, improvements in supportive care and by better risk-group stratifi cation. Th e latter is mainly based on cytogenetics and early response to treatment. In order to survive, children need very intensive chemotherapy, which harbors the risk of severe toxicity and even death during or aft er treatment (5-10% of the cases). Currently, most treatment protocols consist of 4 to 5 blocks of intensive chemotherapy, using a cytarabine and anthracycline backbone. Th e use of stem-cell transplantation aft er complete remission has currently been abandoned by most study groups, since it did not improve survival. Since early-deaths and long-term side eff ect of treatment play an important role, current treatment strategies cannot be intensifi ed. Th erefore, the aim for the future is to design subgroup directed treatment protocols based on the genetic characteristics of pediatric AML to increase survival and reduce toxicity and late eff ects. TWO-HIT MODEL IN DE LEUKEMOGENESIS OF AML Kelly and Gilliland proposed a model in which two classes of abnormalities cooperate to cause AML12. Type-I mutations confer a proliferative signal, which results in a survival advantage for the leukemic cells, whereas type-II mutations induce impairment of hema- topoietic diff erentiation (Figure 2). TYPE-I MUTATIONS IN PEDIATRIC AML Most type-I mutations are involved in kinases or key-players of the RAS-pathway. Th e most important mutations are found in the FLT3-gene, a receptor tyrosine kinase. Th ese aberrations are internal tandem duplications of FLT3 (FLT3-ITD) and mutation in the BBrianrian BBW.inddW.indd 9 331-03-111-03-11 116:596:59 10 Chapter 1 Table 1: WHO-classifi cation 2008 of AML and related precursor neoplasms. AML with recurrent genetic AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 abnormalities AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with t(15;17)(q22;q12); PML-RARA AML with t(9;11)(p22;q23); MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 Provisional entity: AML with mutated NPM1 Provisional entity: AML with mutated CEBPA AML with myelodysplasia- Previously documented MDS or MDS/MPN related changes Specifi c myelodysplasia-related cytogenetic abnormalities Dysplasia in 50% or more of the cells in 2 or more myeloid lineages Th erapy-related myeloid neoplasms Acute myeloid leukemia, not AML with minimal diff erentiation otherwise specifi ed AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofi brosis Myeloid sarcoma Extramedullary proliferation of blasts of one or more of the myeloid lineages that disrupts the normal architecture of the tissue Myeloid proliferations related Transient abnormal myelopoiesis to Down syndrome Myeloid leukemia associated with Down syndrome Blastic plasmacytoid dendritic Blastic NK-cell lymphoma cell neoplasm Table 2: Outcome in pediatric AML from most recent international large studies. Study N 5y-pEFS 5y-EFS ED AML-BFM98 473 50% 62% 3.2% NOPHO-AML93 219 49% 64% 3% MRC12 455 56% 66% 4% LAME91 262 47% 61% 4% AIEOP AML 2002/01 205 55% 70% 4.3% CCG-2961 (regimen C) 406 46% 57% 12% St. Jude AML97 78 49% 54% 4% BBrianrian BBW.inddW.indd 1100 331-03-111-03-11 116:596:59 General Introduction 11 Type-I mutaƟŽŶƐ Type-II mutaƟŽŶƐ PrŽůŝferaƟve advaŶtage: Impaŝred dŝīereŶƟaƟŽŶ: FLT3-ITD, N/K-RAS, MLL-rearraŶgemeŶtƐ, PTPN11, NF1, KIT t(8;21), ŝŶv(16), t(15;17), CEBPA hŶŬŶŽǁŶ: NPM1, WT1, EVI1 Figure 2: Th e diff erent type of aberrations identifi ed in AML tyrosine kinase domain that confer a poor prognosis in pediatric AML13.
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