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Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo.
[hodgkin lymphoma, classical]
Classical
Hodgkin
lymphoma
(
cHL
)
and
primary
mediastinal
large
B-
cell
lymphoma
(
MLBCL
)
share
similar
histologic
,
clinical
,
and
genetic
features
.
In
recent
studies
,
we
found
that
disease-
specific
chromosome
9
p
24
.
1
/
JAK
2
amplification
increased
JAK
2
expression
and
activity
in
both
cHL
and
MLBCL
.
This
prompted
us
to
assess
the
activity
of
a
clinical
grade
JAK
2
selective
inhibitor
,
fedratinib
(
SAR
302503
/
TG
101348
)
,
in
in
vitro
and
in
vivo
model
systems
of
cHL
and
MLBCL
with
defined
JAK
2
copy
numbers
.
We
used
functional
and
immunohistochemical
analyses
to
investigate
the
preclinical
activity
of
fedratinib
and
associated
biomarkers
in
cell
lines
and
murine
xenograft
models
of
cHL
and
MLBCL
with
known
9
p
24
.
1
/
JAK
2
copy
number
.
Chemical
JAK
2
inhibition
decreased
the
cellular
proliferation
of
cHL
and
MLBCL
cell
lines
and
induced
their
apoptosis
.
There
was
an
inverse
correlation
between
9
p
24
.
1
/
JAK
2
copy
number
and
the
EC
50
of
fedratinib
.
Chemical
JAK
2
inhibition
decreased
phosphorylation
of
JAK
2
,
STAT
1
,
STAT
3
,
and
STAT
6
and
reduced
the
expression
of
additional
downstream
targets
,
including
PD-L
1
,
in
a
copy
number-dependent
manner
.
In
murine
xenograft
models
of
cHL
and
MLBCL
with
9
p
24
.
1
/
JAK
2
amplification
,
chemical
JAK
2
inhibition
significantly
decreased
JAK
2
/
STAT
signaling
and
tumor
growth
and
prolonged
survival
.
In
in
vitro
and
in
vivo
studies
,
pSTAT
3
was
an
excellent
biomarker
of
baseline
JAK
2
activity
and
the
efficacy
of
chemical
JAK
2
inhibition
.
In
in
vitro
and
in
vivo
analyses
,
cHL
and
MLBCL
with
9
p
24
.
1
/
JAK
2
copy
gain
are
sensitive
to
chemical
JAK
2
inhibition
suggesting
that
clinical
evaluation
of
JAK
2
blockade
is
warranted
.
Diseases
Validation
Diseases presenting
"prolonged survival"
symptom
alexander disease
cholangiocarcinoma
harlequin ichthyosis
hodgkin lymphoma, classical
krabbe disease
megacystis-microcolon-intestinal hypoperistalsis syndrome
neonatal adrenoleukodystrophy
primary effusion lymphoma
pyruvate dehydrogenase deficiency
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