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FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.
[hodgkin lymphoma, classical]
Recently
we
have
shown
that
the
transcription
factor
FOXO
1
,
highly
expressed
in
B
cells
,
is
downregulated
in
classical
Hodgkin
lymphoma
(
cHL
)
.
As
primary
mediastinal
B
cell
lymphoma
(
PMBL
)
has
similarities
with
the
cHL
transcription
program
we
investigated
FOXO
1
expression
in
this
entity
.
By
using
immunohistochemistry
we
found
that
FOXO
1
was
absent
or
expressed
at
low
levels
in
19
of
20
primary
PMBL
cases
.
PMBL
cell
lines
reproduce
the
low
FOXO
1
expression
observed
in
primary
cases
.
By
analyzing
gene
expression
profiling
data
we
found
that
FOXO
1
expression
inversely
correlated
with
JAK
2
in
PMBL
cases
.
Targeting
JAK
2
activity
by
the
small
molecular
weight
inhibitor
TG
101348
resulted
in
upregulation
of
FOXO
1
mRNA
and
protein
expression
in
MedB-
1
and
U
2940
cell
lines
,
and
the
MYC
inhibitor
10058
-
F
4
increased
FOXO
1
mRNA
in
MedB-
1
cells
.
Moreover
,
in
MedB-
1
cells
FOXO
1
expression
was
strongly
upregulated
by
the
inhibitor
of
DNA
methylation
5
-
aza-
2
-
deoxycytidine
and
by
the
histone
deacetylase
inhibitor
trichostatin
A
.
Since
FOXO
1
promoter
was
unmethylated
,
this
effect
is
most
likely
indirect
.
FOXO
1
activation
in
the
FOXO
1
-
negative
Med-
B
1
cell
line
led
to
growth
arrest
and
apoptosis
,
which
was
accompanied
by
repression
of
MYC
and
BCL
2
L
1
/
BCLxL
.
Thus
,
FOXO
1
repression
might
contribute
to
the
oncogenic
program
and
phenotype
of
PMBL
.
Diseases
Validation
Diseases presenting
"apoptosis"
symptom
22q11.2 deletion syndrome
hodgkin lymphoma, classical
pendred syndrome
primary effusion lymphoma
systemic capillary leak syndrome
waldenström macroglobulinemia
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