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Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors.
[primary effusion lymphoma]
Primary
effusion
lymphoma
(
PEL
)
is
an
aggressive
form
of
non-
Hodgkin
's
B-
cell
lymphoma
associated
with
infection
by
Kaposi
's
sarcoma
-associated
herpes
virus
(
KSHV
)
.
(
+
)
-
JQ
1
and
I
-
BET
1
51
are
two
recently
described
novel
small
-molecule
inhibitors
of
BET
bromodomain
chromatin-associated
proteins
that
have
shown
impressive
preclinical
activity
in
cancers
in
which
MYC
is
overexpressed
at
the
transcriptional
level
due
to
chromosomal
translocations
that
bring
the
MYC
gene
under
the
control
of
a
super-enhancer
.
PEL
cells
,
in
contrast
,
lack
structural
alterations
in
the
MYC
gene
,
but
have
deregulated
Myc
protein
due
to
the
activity
of
KSHV-encoded
latent
proteins
.
We
report
that
PEL
cell
lines
are
highly
sensitive
to
bromodomain
and
extra
-terminal
(
BET
)
bromodomain
inhibitors-induced
growth
inhibition
and
undergo
G
0
/
G
1
cell-cycle
arrest
,
apoptosis
and
cellular
senescence
,
but
without
the
induction
of
lytic
reactivation
,
upon
treatment
with
these
drugs
.
Treatment
of
PEL
cell
lines
with
BET
inhibitors
suppressed
the
expression
of
MYC
and
resulted
in
a
genome-
wide
perturbation
of
MYC
-dependent
genes
.
Silencing
of
BRD
4
and
MYC
expression
blocked
cell
proliferation
and
cell-cycle
progression
,
while
ectopic
expression
of
MYC
from
a
retroviral
promoter
rescued
cells
from
(
+
)
-
JQ
1
-
induced
growth
arrest
.
In
a
xenograft
model
of
PEL
,
(
+
)
-
JQ
1
significantly
reduced
tumor
growth
and
improved
survival
.
Taken
collectively
,
our
results
demonstrate
that
the
utility
of
BET
inhibitors
may
not
be
limited
to
cancers
in
which
genomic
alterations
result
in
extremely
high
expression
of
MYC
and
they
may
have
equal
or
perhaps
greater
activity
against
cancers
in
which
the
MYC
genomic
locus
is
structurally
intact
and
c-
Myc
protein
is
deregulated
at
the
post-translational
level
and
is
only
modestly
overexpressed
.
Diseases
Validation
Diseases presenting
"significantly reduced tumor growth"
symptom
primary effusion lymphoma
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