Epigenetics in MLL-rearranged Infant Acute Lymphoblastic Leukemia

272 Pages·2012·36.47 MB·English

Epigenetics in MLL-rearranged
Infant Acute Lymphoblastic Leukemia
Dominique J.P.M. Stumpel
ISBN: 978-94-6182-133-1
Author: Dominique J.P.M. Stumpel
Cover images: Mathé A.J.M. Prick, beeldend kunstenaar
Lay-out and Printing: Offpage (www.offpage.nl)
The work described in this thesis was performed at the Department of
Pediatric Oncology/Hematology of the Erasmus MC-Sophia Children’s
Hospital, Rotterdam, the Netherlands. The studies described in
this thesis were financially supported by grants from the Sophia
Foundation for Medical Research (SSWO grants 495 and 600).
We gratefully acknowledge Amgen, Celgene, the Erasmus University
Rotterdam (EUR), Eusapharma, Janssen-Cilag, the Jurriaanse
Foundation, MosaMedix, MRC Holland, NeXins Research, Novartis,
the Pediatric Oncology Foundation Rotterdam (KOCR), and Sanofi for
providing financial support for the printing of this thesis.
Copyright © 2012, Dominique Stumpel,
Rotterdam, the Netherlands.
No part of the material protected by this copyright notice may be
reproduced, stored in a retrieval system or transmitted in any form or
by any means, without prior written permission of the author or, when
appropriate, from the publishers of the papers included in this book.
Epigenetics in MLL-rearranged
Infant Acute Lymphoblastic Leukemia
Epigenetica van MLL-herschikte
acute lymfatische leukemie bij zuigelingen
Proefschrift
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de rector magnificus
Prof. dr. H.G. Schmidt
en volgens besluit van het College voor Promoties
De openbare verdediging zal plaatsvinden op
woensdag 5 september 2012 om 15.30 uur
door
Dominique Jacoba Pauline Maria Stumpel
geboren te Breda
PROMOTIECOMMISSIE:
Promotor:
Prof. dr. R. Pieters
Overige leden:
Prof. dr. E.C. Zwarthoff
Prof. dr. E. Dzierzak
Prof. dr. H.R. Delwel
Co-promotor:
Dr. R.W. Stam
“Do not go where the path may lead,
go instead where there is no path and leave a trail.”
(Ralph Waldo Emerson)
I lovingly dedicate this thesis to my parents,
who supported me each step of the way
I also dedicate this thesis to the memory of Brian, whose
optimism, zest for life and inner strength
was an inspiration for all of us
“Our lost friends are not death, but gone before, advanced a stage
of two upon that road which we must travel in the steps they trod.”
(Aristophanes)
IN MEMORIAM
Brian Robert Hermand van Westing
Bri/ Doc
In Memoriam page
Final page acknowledgments
September 27, 1978 March 27, 2009

COnTEnTS
Prologue 11
Chapter 1 General Introduction, Aims and Scope of this Thesis. 13
Part I: Aberrant DNA Methylation 37
Chapter 2 Specific Promoter Methylation Identifies Different
Subgroups of MLL-rearranged Infant Acute Lymphoblastic
Leukemia, Influences Clinical Outcome and Provides
Therapeutic Options. 39
Chapter 3 Aberrant Methylation at MicroRNA Loci 61
3.1 Differential MicroRNA Methylation among Subtypes
of MLL-rearranged Infant Acute Lymphoblastic Leukemia. 63
3.2 Hypermethylation of Specific MicroRNA Genes
in MLL-rearranged Infant Acute Lymphoblastic Leukemia:
Major Matters at a Micro Scale. 69
Chapter 4 Absence of Global Hypomethylation in Promoter
Hypermethylated MLL-rearranged Infant Acute
Lymphoblastic Leukemia. 93
Part II: Therapeutic Implications 113
Chapter 5 The Potential of Clofarabine in MLL-rearranged Infant
Acute Lymphoblastic Leukemia. 115
Chapter 6 Connectivity Mapping Identifies HDAC Inhibitors
for the Treatment of t(4;11)-positive Infant Acute
Lymphoblastic Leukemia. 139
Epilogue 165
Chapter 7 MLL-rearranged Infant Acute Lymphoblastic Leukemia:
An Epigenetic Disease which Should Be Treated Accordingly.
General Discussion and Future Perspectives 167
Chapter 8 Bullet Point Summary 189
Chapter 9 Layman’s Summary in Dutch
Nederlandse samenvatting voor niet-ingewijden 193
Chapter 10 Abbreviations 207
Chapter 11 Affiliations Co-authors 211
Chapter 12 Acknowledgments
Dankwoord 215
About the Author 231
List of Publications 233
PhD Portfolio 235
Curriculum Vitae (English) 241
Curriculum Vitae (Dutch) 243
Appendices 245
Supplemental methods 246
Supplemental figures and tables 250