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Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma show alterations of genes encoding the NADPH oxidase complex and impaired reactive oxygen species synthesis capacity.
[hodgkin lymphoma, classical]
The
membrane
bound
NADPH
oxidase
involved
in
the
synthesis
of
reactive
oxygen
species
(
ROS
)
is
a
multi-protein
enzyme
encoded
by
CYBA
,
CYBB
,
NCF
1
,
NCF
2
and
NCF
4
genes
.
Growing
evidence
suggests
a
role
of
ROS
in
the
modulation
of
signaling
pathways
of
non-phagocytic
cells
,
including
differentiation
and
proliferation
of
B-
cell
progenitors
.
Transcriptional
downregulation
of
the
CYBB
gene
has
been
previously
reported
in
cell
lines
of
the
B-
cell
derived
classical
Hodgkin
lymphoma
(
cHL
)
.
Thus
,
we
explored
functional
consequences
of
CYBB
downregulation
on
the
NADPH
complex
.
Using
flow
cytometry
to
detect
and
quantify
superoxide
anion
synthesis
in
cHL
cell
lines
we
identified
recurrent
loss
of
superoxide
anion
production
in
all
stimulated
cHL
cell
lines
in
contrast
to
stimulated
non-
Hodgkin
lymphoma
cell
lines
.
As
CYBB
loss
proved
to
exert
a
deleterious
effect
on
the
NADPH
oxidase
complex
in
cHL
cell
lines
,
we
analyzed
the
CYBB
locus
in
Hodgkin
and
Reed
-
Sternberg
(
HRS
)
cells
of
primary
cHL
biopsies
by
in
situ
hybridisation
and
identified
recurrent
deletions
of
the
gene
in
8
/
18
cases
.
Immunohistochemical
analysis
to
14
of
these
cases
revealed
a
complete
lack
of
detectable
CYBB
protein
expression
in
all
HRS
cells
in
all
cases
studied
.
Moreover
,
by
microarray
profiling
of
cHL
cell
lines
we
identified
additional
alterations
of
NADPH
oxidase
genes
including
CYBA
copy
number
loss
in
3
/
7
cell
lines
and
a
significant
downregulation
of
the
NCF
1
transcription
(
p
=
0
.
006
)
compared
to
normal
B-
cell
subsets
.
Besides
,
NCF
1
protein
was
significantly
downregulated
(
p
<
0
.
005
)
in
cHL
compared
to
other
lymphoma
cell
lines
.
Together
this
findings
show
recurrent
alterations
of
the
NADPH
oxidase
encoding
genes
that
result
in
functional
inactivation
of
the
enzyme
and
reduced
production
of
superoxide
anion
in
cHL
.