Table Of ContentCover
design
my
mother
An
Van
de
Vel
II
FACULTY
OF
MEDICINE
AND
HEALTH
SCIENCES
Ghent
University,
Faculty
of
Medicine
and
Health
Sciences
Lost
in
Transcription
Emergence
of
Epigenetic
Drivers
and
MicroRNAs
in
T-‐cell
Acute
Lymphoblastic
Leukemia
This
thesis
is
submitted
as
fulfillment
of
the
requirements
for
the
degree
of
Doctor
in
Medical
Sciences
by
ir.
Joni
Van
der
Meulen,
2014
Promotor
prof.
dr.
Frank
Speleman
Co-‐promotor
prof.
dr.
Yves
Benoit
Center
for
Medical
Genetics
Ghent
University
Hospital,
Medical
Research
Building
De
Pintelaan
185,
9000
Gent,
Belgium
+32-‐9-‐3326950
[email protected]
III
IV
Thesis
submitted
to
fulfill
the
requirements
for
the
degree
of
Doctor
in
Medical
Sciences
Promotor:
prof.
dr.
Frank
Speleman
Ghent
University,
Belgium
Co-‐promotor:
prof.
dr.
Yves
Benoit
Ghent
University,
Belgium
Members
of
the
examination
committee:
prof.
dr.
Omar
I.
Abdel-‐Wahab
Memorial
Sloan-‐Kettering
Cancer
Center,
NY,
USA
prof.
dr.
Jan
Cools
KULeuven,
Belgium
dr.
Tom
Van
Maerken
Ghent
University,
Belgium
prof.
dr.
Tessa
Kerre
Ghent
University,
Belgium
dr.
Steven
Goossens
Ghent
University,
Belgium
dr.
ir.
Pieter
Mestdagh
Ghent
University,
Belgium
prof.
dr.
Marc
Bracke
Ghent
University,
Belgium
De
auteur
en
de
promotoren
geven
de
toelating
deze
scriptie
voor
consultatie
beschikbaar
te
stellen
en
delen
ervan
te
kopiëren
voor
persoonlijk
gebruik.
Elke
ander
gebruik
valt
onder
de
beperkingen
van
het
auteursrecht,
in
het
bijzonder
met
betrekking
tot
de
verplichting
uitdrukkelijk
de
bron
te
vermelden
bij
het
aanhalen
van
resultaten
uit
deze
scriptie.
The
author
and
the
promoters
give
the
permission
to
use
this
thesis
for
consultation
and
to
copy
parts
of
it
for
personal
use.
Every
other
use
is
subject
to
the
copyright
law,
more
specifically
the
source
must
be
extensively
specified
when
using
results
from
this
thesis.
The
research
described
in
this
thesis
was
conducted
at
the
Center
for
Medical
Genetics,
Ghent
University
Hospital,
Ghent,
Belgium.
This
work
was
supported
by
the
Fund
for
Scientific
Research
(FWO)
Flanders
(PhD
grant
to
Joni
Van
der
Meulen
and
project
grants);
the
Flemish
Liga
against
Cancer
(VLK)
(Emmanuel
van
der
Schueren
scholarship
to
Joni
Van
der
Meulen);
the
GOA-‐UGent;
Belgian
Foundation
against
Cancer,
the
Cancer
Plan
from
the
Federal
Public
Service
of
Health;
the
Children
Cancer
Fund
Ghent;
the
Belgian
Program
of
Interuniversity
Poles
of
Attraction
IUAP;
the
Belgian
Foundation
Against
Cancer.
V
VI
This
thesis
is
dedicated
to
my
father
my
mother
and
sister
my
grandparents
my
family
and
friends
VII
VIII
Table
of
Contents
List
of
abbreviations
__________________________________________________
1
Chapter
1.
Introduction
_______________________________________________
3
PART
I
____________________________________________________________________
5
1.
The
genomic
landscape
of
T-‐cell
acute
lymphoblastic
leukemia
_____________________
5
1.1
Molecular-‐genetic
T-‐ALL
subgroups
......................................................................
6
1.2
Defects
across
the
T-‐ALL
subgroups
......................................................................
7
Defects
in
the
NOTCH1
signaling
pathway
8
Defects
in
the
MYB
signaling
pathway
9
2.
The
epigenomic
landscape
of
T-‐cell
acute
lymphoblastic
leukemia
and
links
with
therapeutical
options
_______________________________________________________
11
2.1
DNA
methylation
.................................................................................................
11
2.2
Nucleosome
remodeling
.....................................................................................
13
2.3
Histone
variants
..................................................................................................
14
2.4
Histone
modifications
&
their
mediators
............................................................
14
The
putative
histone
reader
PHF6
15
The
Polycomb
repressor
complexes
PRC1
&
PRC2
17
The
H3K27me3
demethylase
UTX
19
The
H3K4me3
histone
methyltransferases
MLL1
&
MLL2
20
The
histone
acetyltransferase
EP300
20
The
H3K36me3
histone
methyltransferase
SETD2
21
2.5
Intimately
linked
epigenetic
modifications
.........................................................
21
3.
The
microRNAome
of
T-‐cell
acute
lymphoblastic
leukemia
_______________________
22
3.1
MicroRNA
biogenesis
&
function
........................................................................
22
3.2
MicroRNAs
in
T-‐cell
acute
lymphoblastic
leukemia
............................................
23
3.3
MicroRNA
biomarkers
&
therapeutics
................................................................
24
References
_______________________________________________________________
26
PART
II
___________________________________________________________________
39
1.
Review:
The
H3K27me3
demethylase
UTX
in
normal
development
and
disease
_______
39
Chapter
2.
Research
Objectives
________________________________________
57
Chapter
3.
Results
__________________________________________________
61
1.
Epigenetic
drivers
in
T-‐cell
acute
lymphoblastic
leukemia
________________________
63
Paper
1.
PHF6
mutations
in
T-‐cell
acute
lymphoblastic
leukemia
............................
65
Paper
2.
The
H3K27me3
demethylase
UTX
is
a
gender-‐specific
tumor
suppressor
in
T-‐cell
acute
lymphoblastic
leukemia
...................................................
83
2.
MicroRNAs
in
T-‐cell
acute
lymphoblastic
leukemia
_____________________________
117
Paper
3.
A
cooperative
microRNA
–
tumor
suppressor
gene
network
in
acute
T-‐cell
lymphoblastic
leukemia
(T-‐ALL)
...........................................................
119
Paper
4.
MicroRNA-‐193b-‐3p
acts
as
a
tumor
suppressor
by
targeting
the
MYB
oncogene
in
T-‐cell
acute
lymphoblastic
leukemia
..........................................
155
Chapter
4.
Discussion
&
Future
perspectives
____________________________
189
Summary
_________________________________________________________
205
Samenvatting
_____________________________________________________
207
Dankwoord
_______________________________________________________
209
Curriculum
Vitae
__________________________________________________
211
IX
X
Description:Using karyotyping, fluorescence in-‐situ hybridization (FISH), array comparative The introduction of targeted and next-‐generation sequencing techniques In a collaborative effort with the Wendel lab (MSKCC, NY, USA), we further HOX-specific ultra-dense tiling microarrays (ChIP-chip) showed.
