Constitutive systemic inflammation in Shwachman-Diamond Syndrome
Molecular Medicine,
Journal Year:
2025,
Volume and Issue:
31(1)
Published: Feb. 28, 2025
Abstract
Background
and
purpose
Shwachman-Diamond
Syndrome
(SDS)
is
an
autosomal
recessive
disease
belonging
to
the
inherited
bone
marrow
failure
syndromes
characterized
by
hypocellular
marrow,
exocrine
pancreatic
insufficiency,
skeletal
abnormalities.
SDS
associated
with
increased
risk
of
developing
myelodysplastic
syndrome
(MDS)
and/or
acute
myeloid
leukemia
(AML).
Although
not
primarily
considered
inflammatory
disorder,
some
conditions
(e.g.,
neutropenia,
pancreatitis
dysfunction)
may
involve
inflammation
or
immune
system
dysfunctions.
We
have
already
demonstrated
that
signal
transducer
activator
transcription
(STAT)-3
mammalian
target
rapamycin
(mTOR)
were
hyperactivated
elevated
IL-6
levels
in
leukocytes.
In
this
study,
we
analyzed
level
phosphoproteins
involved
STAT3
mTOR
pathways
lymphoblastoid
cells
(LCLs)
secretomic
profile
soluble
pro-inflammatory
mediators
plasma
LCLs
order
investigate
systemic
these
patients
relative
pathways.
Methods
Twenty-six
seven
healthy
donors
comparable
age
recruited
during
programmed
follow-up
visits
for
clinical
evaluation
at
Verona
Cystic
Fibrosis
Center
Human.
The
obtained
samples
(plasma
LCLs)
for:
phosphoproteins,
cytokines,
chemokines
growth
factors
Bio-plex
technology;
microRNAs
profiling
next
generation
sequencing
(NGS)
expression
validation
Real
Time-PCR
(RT-PCR)
droplet
digital
PCR
(ddPCR)
.
Results
dysregulation
ERK1/2
AKT
SDS,
as
their
involvement
hyperactivation
confirmed
interplay
pathophysiology.
However,
both
signaling
are
strongly
influenced
environment.
Here,
reported
several
proinflammatory
mediators.
vitro
experiments
show
genes
closely
correlated
STAT3/mTOR
pathway
activation.
addition,
found
miR-181a-3p
down-regulated
SDS.
Since
miRNA
acts
a
regulator
such
ERK1/2,
its
down-regulation
be
driver
constitutive
observed
patients.
Conclusions
results
study
shed
light
on
complex
pathogenetic
mechanism
underlying
leukemogenesis
suggesting
need
anti-inflammatory
therapies
Language: Английский
Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure
Journal of Clinical Investigation,
Journal Year:
2025,
Volume and Issue:
135(6)
Published: March 16, 2025
Inherited
bone
marrow
failure
syndromes
(IBMFSs)
encompass
a
diverse
group
of
hematological
disorders
characterized
by
progressive
single-lineage
cytopenia
or
pancytopenia.
Despite
their
heterogeneity,
these
often
result
from
genetic
errors
affecting
key
biological
mechanisms,
including
telomere
maintenance,
DNA
repair
and
chromosomal
stability,
ribosome
assembly,
generally
leading
to
accelerated
apoptosis
hematopoietic
cells.
Nevertheless,
diagnosis
remains
elusive
in
more
than
half
the
cases.
The
increased
risk
myelodysplastic
syndrome
(MDS),
acute
leukemia,
solid
tumors
associated
with
IBMFS
frequently
prompts
early
stem
cell
transplantation
(HSCT).
In
this
issue
JCI,
Garrigue,
Kermasson,
colleagues
identified
homozygous
variant
Oncostatin
M
(OSM)
3
children
consanguineous
family
presenting
profound
anemia,
thrombocytopenia,
neutropenia.
findings
suggest
that
loss-of-function
OSM
affected
function
through
changes
microenvironment
(BMM).
Language: Английский
Harnessing Single-Cell Technologies in the Search for New Therapies for Diamond–Blackfan Anemia Syndrome
Experimental Hematology,
Journal Year:
2024,
Volume and Issue:
135, P. 104235 - 104235
Published: May 11, 2024
The
emergence
of
multi-omic
single-cell
technologies
over
the
last
decade
has
led
to
improved
insights
into
both
normal
hematopoiesis
and
its
perturbation
in
a
variety
hematological
disorders.
Diamond-Blackfan
anemia
(DBA)
is
one
such
disorder
where
assays
have
helped
delineate
cellular
molecular
defects
underlying
disease.
DBA
caused
by
heterozygous
loss
function
germline
variants
genes
encoding
ribosomal
proteins
(RPs).
Despite
widespread
role
ribosomes
hematopoiesis,
most
frequent
severe
cytopenia
anemia.
In
this
review
we
will
discuss
how
single
cell
studies-
including
clonogenic
culture
assays,
fluorescence
activated
sorting
(FACS)
RNA
sequencing
(scRNAseq)-have
pathogenesis
DBA.
main
therapies
are
regular
blood
transfusions,
glucocorticoids
or
hematopoietic
stem
transplantation
(HSCT)
but
all
associated
with
significant
morbidity
mortality.
We
therefore
outline
studies
can
inform
new
for
Furthermore,
serves
as
useful
model
understanding
erythropoiesis
terms
hierarchy,
regulation
during
homeostasis
response
'stress'.
Language: Английский
Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management
Journal of Clinical Medicine,
Journal Year:
2023,
Volume and Issue:
12(22), P. 7185 - 7185
Published: Nov. 20, 2023
Irreversible
severe
bone
marrow
failure
(BMF)
is
a
life-threatening
condition
in
pediatric
patients.
Most
important
causes
are
inherited
syndromes
(IBMFSs)
and
(pre)malignant
diseases,
such
as
myelodysplastic
syndrome
(MDS)
(idiopathic)
aplastic
anemia
(AA).
Timely
treatment
essential
to
prevent
infections
bleeding
complications
increase
overall
survival
(OS).
Allogeneic
hematopoietic
stem
cell
transplantation
(HSCT)
provides
cure
for
most
types
of
BMF
but
cannot
restore
non-hematological
defects.
When
using
matched
sibling
donor
(MSD)
or
unrelated
(MUD),
the
OS
after
HSCT
ranges
between
60
90%.
Due
introduction
post-transplantation
cyclophosphamide
(PT-Cy)
graft
versus
host
disease
(GVHD),
alternative
can
reach
similar
rates.
Although
ineffective
hematopoiesis,
it
not
always
used
first-line
therapy
due
risks
associated
with
HSCT.
Therefore,
depending
on
underlying
cause,
other
options
might
be
preferred.
Finally,
IBMFSs
an
identified
genetic
etiology,
gene
provide
novel
strategy
could
bypass
certain
limitations
However,
still
its
infancy.
This
review
summarizes
current
clinical
practices
BMF,
including
well
disease-specific
options.
Language: Английский
New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(21), P. 11619 - 11619
Published: Oct. 29, 2024
Fanconi
anemia
(FA)
represents
a
rare
hereditary
disease;
it
develops
due
to
germline
pathogenic
variants
in
any
of
the
22
currently
discovered
FANC
genes,
which
interact
with
anemia/breast
cancer-associated
(FANC/BRCA)
pathway
maintain
genome
integrity.
FA
is
characterized
by
triad
clinical
traits,
including
congenital
anomalies,
bone
marrow
failure
(BMF)
and
multiple
cancer
susceptibility.
Due
complex
genetic
background
broad
spectrum
symptoms,
diagnostic
process
requires
use
classical
cytogenetic,
molecular
cytogenetics
strictly
methods.
Recent
findings
indicate
interplay
inflammation,
oxidative
stress,
disrupted
mitochondrial
metabolism,
impaired
intracellular
signaling
pathogenesis.
Additionally,
shift
balance
towards
overproduction
proinflammatory
cytokines
prooxidant
components
associated
advanced
myelosuppression
ultimately
BMF.
Although
mechanism
BMF
very
needs
further
clarification,
appears
that
mutual
interaction
between
redox
imbalance
causes
pancytopenia.
In
this
review,
we
summarize
available
literature
regarding
phenotype,
background,
procedures
FA.
We
also
highlight
current
understanding
autophagy
process,
state,
pathways
genotoxic
stress
Language: Английский