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CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease.
[severe combined immunodeficiency]
Secreted
protein
CCN
1
,
encoded
by
CYR
61
,
is
involved
in
wound
healing
,
angiogenesis
,
and
osteoblast
differentiation
.
We
identified
CCN
1
as
a
microenvironmental
factor
produced
by
mesenchymal
cells
and
overexpressed
in
bones
of
a
subset
of
patients
with
monoclonal
gammopathy
of
undetermined
significance
(
MGUS
)
,
asymptomatic
myeloma
(
AMM
)
,
and
multiple
myeloma
(
MM
)
.
Our
analysis
showed
that
overexpression
of
CYR
61
was
independently
associated
with
superior
overall
survival
of
MM
patients
enrolled
in
our
Total
Therapy
3
protocol
.
Moreover
,
elevated
CCN
1
was
associated
with
a
longer
time
for
MGUS
/
AMM
to
progress
to
overt
MM
.
During
remission
from
MM
,
high
levels
of
CCN
1
were
associated
with
superior
progression-free
and
overall
survival
and
stratified
patients
with
molecularly
defined
high
-risk
MM
.
Recombinant
CCN
1
directly
inhibited
in
vitro
growth
of
MM
cells
,
and
overexpression
of
CYR
61
in
MM
cells
reduced
tumor
growth
and
prevented
bone
destruction
in
vivo
in
severe
combined
immunodeficiency
-
hu
mice
.
Signaling
through
αvβ
3
was
required
for
CCN
1
prevention
of
bone
disease
.
CYR
61
expression
may
signify
early
perturbation
of
the
microenvironment
before
conversion
to
overt
MM
and
may
be
a
compensatory
mechanism
to
control
MM
progression
.
Therapeutics
that
upregulate
CYR
61
should
be
investigated
for
treating
MM
bone
disease
.
