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MYD88-independent growth and survival effects of Sp1 transactivation in Waldenstrom macroglobulinemia.
[waldenström macroglobulinemia]
Sp
1
transcription
factor
controls
a
pleiotropic
group
of
genes
and
its
aberrant
activation
has
been
reported
in
a
number
of
malignancies
,
including
multiple
myeloma
.
In
this
study
,
we
investigate
and
report
its
aberrant
activation
in
Waldenström
macroglobulinemia
(
WM
)
.
Both
loss
of
and
gain
of
Sp
1
function
studies
have
highlighted
a
potential
oncogenic
role
of
Sp
1
in
WM
.
We
have
further
investigated
the
effect
of
a
small
molecule
inhibitor
,
terameprocol
(
TMP
)
,
targeting
Sp
1
activity
in
WM
.
Treatment
with
TMP
inhibited
the
growth
and
survival
and
impaired
nuclear
factor
-
κ
B
and
signal
transducer
and
activator
of
transcription
activity
in
WM
cells
.
We
next
investigated
and
observed
that
TMP
treatment
induced
further
inhibition
of
WM
cells
in
MYD
88
knockdown
WM
cells
.
Moreover
,
we
observed
that
Bruton
's
tyrosine
kinase
,
a
downstream
target
of
MYD
88
signaling
pathway
,
is
transcriptionally
regulated
by
Sp
1
in
WM
cells
.
The
combined
use
of
TMP
with
Bruton
's
tyrosine
kinase
or
interleukin-
1
receptor-associated
kinase
1
and
4
inhibitors
resulted
in
a
significant
and
synergistic
dose-dependent
antiproliferative
effect
in
MYD
88
-
L
265
P-
expressing
WM
cells
.
In
summary
,
these
results
demonstrate
Sp
1
as
an
important
transcription
factor
that
regulates
proliferation
and
survival
of
WM
cells
independent
of
MYD
88
pathway
activation
,
and
provide
preclinical
rationale
for
clinical
development
of
TMP
in
WM
alone
or
in
combination
with
inhibitors
of
MYD
88
pathway
.
Diseases
Validation
Diseases presenting
"small molecule inhibitor"
symptom
dedifferentiated liposarcoma
systemic capillary leak syndrome
waldenström macroglobulinemia
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