Gene-expression profiles and oncogenes in pediatric T-cell acute lymphoblastic leukemia

239 Pages·2011·34.85 MB·English

Gene-expression profiles and oncogenes
in pediatric T-cell acute lymphoblastic leukemia
Gratitude is expressed to the Dutch Cancer Society (KWF kankerbestrijding) and
the Pediatric Oncology Foundation Rotterdam (KOCR) for financial support of the
print and reproduction of this thesis.

The research was financially supported by the Dutch Cancer Society (EMCR 2006-
3500).

Printed by Drukkerij Van Denderen, Groningen
ISBN: 978-90-9026438-7

Copyright © I. Homminga, Groningen, the Netherlands, 2011
All rights reserved. No part of this thesis may be reproduced or transmitted to any
form, by any means, electronic or mechanical, without the prior written permission
of the author
Gene-expression profiles and oncogenes
in pediatric T-cell acute lymphoblastic leukemia

Gen-expressie profielen en oncogenen
in T-cel acute lymfatische leukemie bij kinderen

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 30 november 2011 om 15:30
door
Irene Homminga
geboren te Groningen
Promotiecomissie

Promotor: Prof. dr. R. Pieters
Overige leden: Prof. dr. J. Cornelissen
Dr. M.L. den Boer
Dr. A.W. Langerak
Copromotor: Dr. J.P.P. Meijerink
Voor Hans
Max & Henk

CONTENTS
General introduction 9
Chapter 1: Integrated transcript and genome analyses reveal NKX2-1 27
and MEF2C as potential oncogenes in T cell acute
lymphoblastic leukemia.
Chapter 2: Characterization of a pediatric T-cell acute lymphoblastic 57
leukemia patient with simultaneous LYL1 and LMO2
rearrangements.
Chapter 3: Cooperative genetic defects in TLX3 rearranged 67
pediatric T-ALL
Chapter 4: NKL homeobox genes in leukemia 89
Chapter 5: NOTCH1 and/or FBXW7 mutations predict for initial 119
good prednisone response but not for improved outcome
in pediatric T-cell acute lymphoblastic leukemia patients
treated on DCOG or COALL protocols
Chapter 6: In vitro efficacy of forodesine and nelarabine (ara-G) in 143
pediatric leukemia
Summary, general discussion and future perspectives 165
Nederlandse samenvatting voor de leek 177

About the author 185
(Curriculum vitae, List of publications, PhD portfolio)

Dankwoord 191
Color Figures 197
Supplementary Data 211

General introduction
General introduction
1. GENERAL INTRODUCTION

1.1 Blood & leukemia
Blood consists of serum and three other main ingredients: erythrocytes (red blood
cells), thrombocytes (platelets) and leukocytes (white blood cells). Leukocytes
normally compose less than 1% of the blood volume but have important functions
in our defense against foreign and endogenous pathogens. Many different
leukocytes can be distinguished, the main types being lymphocytes (~75% T-cells,
~25% B-cells), monocytes and granulocytes1. All these different blood cells arise
through distinct and tightly controlled developmental stages from hematopoietic
precursor cells, which reside in the bone marrow and thymus (Figure 1). However,
sequential mutations, chromosomal rearrangements and epigenetic changes can
cause a precursor cell to be blocked from further differentiation and to start
proliferate in a uncontrollable manner which results in cancer. Uncontrolled
proliferation of blood precursor cells is called leukemia. Different types of
leukemia are distinguished based on their lineage of origin; myeloid or
lymphoblastic leukemia. Lymphoblastic leukemia can be further divided into B-
cell precursor (BCP) or T-cell lymphoblastic leukemia. In acute lymphoblastic
leukemia malignant cells are arrested at a relative immature stage whereas in
chronic lymphocytic leukemia, cells have a more differentiated phenotype.
1.2 Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is the most common type of cancer in
children, comprising approximately 25% of all childhood malignancies.2 Patients
usually present with nonspecific symptoms. Most of these can be explained by the
accumulation of leukemic lymphoblasts in the bone marrow, which repress the
development of normal, healthy, blood cells. These symptoms can be fever (due to
normal leukocyte deficiency), fatigue (due to erythrocyte deficiency) and bleeding
(due to thrombocyte deficiency). Infiltration of leukemic cells to sites outside the
bone marrow can lead to other symptoms such as bone pain (caused by infiltration
of the periosteum), lymphadenopathy (caused by infiltration of the lymph nodes)
and headache (caused by infiltration of the central nervous system). Without
treatment, leukemia is lethal. Therapy has become more and more effective over
the years and the survival of ALL patients has increased to about 80%3. Therapy
consists mainly of combination chemotherapy.
10