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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
"hodgkin lymphoma"
symptom
esophageal adenocarcinoma
hodgkin lymphoma, classical
monosomy 21
primary effusion lymphoma
severe combined immunodeficiency
systemic capillary leak syndrome
waldenström macroglobulinemia
This symptom has already been validated