Characterization and targeting of the NF-kB pathway in non-Hodgkin lymphoma
Author
Odqvist, LinaAdvisor
Piris Pinilla, Miguel ÁngelEntity
UAM. Departamento de Biología MolecularDate
2013-11-27Subjects
Linfomas no Hodgkin - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita, leída en Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 27/11/2013Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
NF-‐κB
is
a
family
of
transcription
factors
responsible
for
the
regulation
of
hundreds
of
genes
controlling
key
cellular
processes
such
as
proliferation,
apoptosis
and
inflammation.
The
activation
of
NF-‐κB
is
an
Achilles
heel
of
many
lymphoid
malignancies.
Therefore,
a
lot
of
effort
is
being
made
in
investigating
its
regulatory
mechanisms
and
exploring
its
therapeutic
potentials.
In
this
doctoral
thesis,
we
have
investigated
the
NF-‐κB
pathway
in
non-‐Hodgkin
lymphomas,
with
the
aim
of
characterizing
its
expression
and
clinical
impact
in
human
lymphomas
and
identifying
putative
molecular
targets
able
to
interfere
with
its
activation
and
lymphoma
cell
survival.
Abnormal
NF-‐κB
activation
has
been
linked
to
Diffuse
Large
B-‐cell
Lymphoma
(DLBCL)
and
has
been
described
to
play
a
key
role
in
the
pathogenesis
of
a
specific
molecular
subtype
of
this
malignancy,
the
ABC-‐DLBCL.
In
the
first
part
of
this
work,
we
evaluated
the
expression
of
NF-‐κB
by
immunohistochemistry
in
a
large
series
of
DLBCL
cases.
The
five
different
family
members
showed
a
heterogeneous
and
intricate
expression
pattern,
but
most
remarkably,
NF-‐κB
signaling
was
found
to
be
a
prominent
feature
not
only
in
ABC-‐DLBCL,
but
also
in
GCB-‐
DLBCL,
a
subtype
of
DLBCL
previously
described
to
lack
NF-‐κB
activation.
Furthermore,
c-‐Rel
expression
was
observed
as
a
common
feature
in
DLBCL
and
was
able
to
identify
a
subset
of
patients
with
enhanced
overall
survival.
Peripheral
T-‐cell
lymphomas
(PTCL)
are
highly
aggressive
tumors
with
a
current
lack
of
effective
therapies,
partly
due
to
its
unknown
molecular
pathology.
In
the
second
part
of
this
work,
we
investigated
the
function
of
the
NF-‐κB–inducing
kinase
(NIK)
in
NF-‐κB
signaling
and
its
potential
as
a
molecular
target
in
T-‐cell
lymphomas.
We
showed
that
the
NF-‐κB
pathway
was
activated
in
a
subset
of
PTCLs
associated
with
poor
overall
survival.
NIK
was
overexpressed
in
a
number
of
PTCL
cell
lines
and
primary
samples
and
a
role
for
NIK
as
a
critical
regulator
of
both
classical
and
alternative
NF-‐κB
activation
was
unveiled.
Using
genetic
silencing,
we
demonstrated
a
pivotal
role
for
NIK
in
the
survival
of
these
tumor
cells
as
NIK
depletion
led
to
a
dramatic
induction
of
apoptosis
in
NIK-‐overexpressing
cells.
The
knockdown
of
NIK
led
to
a
modulation
of
several
key
factors
in
cancer
cell
survival
and
apoptosis
evasion
and
had
also
an
impact
on
other
important
survival
pathways,
apart
from
NF-‐κB,
in
PTCL
pathogenesis.
The
results
of
this
part
of
the
study
indicate
that
NIK
could
be
a
promising
therapeutic
target
in
these
aggressive
malignancies.
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