Nature Genetics,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Jan. 17, 2024
Abstract
Myeloproliferative
neoplasms
(MPNs)
are
chronic
cancers
characterized
by
overproduction
of
mature
blood
cells.
Their
causative
somatic
mutations,
for
example,
JAK2
V617F
,
common
in
the
population,
yet
only
a
minority
carriers
develop
MPN.
Here
we
show
that
inherited
polygenic
loci
underlie
hematological
traits
influence
clonal
expansion.
We
identify
risk
scores
(PGSs)
monocyte
count
and
plateletcrit
as
new
factors
positivity.
PGSs
several
influenced
different
MPN
subtypes,
with
low
two
platelet
also
showing
protective
effects
carriers,
making
them
to
three
times
less
likely
have
essential
thrombocythemia
than
high
PGSs.
observed
extreme
may
contribute
an
diagnosis
absence
driver
mutations.
Our
study
showcases
how
backgrounds
underlying
both
selection
on
mutations
subsequent
phenotype
cancer.
New England Journal of Medicine,
Journal Year:
2023,
Volume and Issue:
388(26), P. 2422 - 2433
Published: May 4, 2023
Telomere
shortening
is
a
well-characterized
cellular
aging
mechanism,
and
short
telomere
syndromes
cause
age-related
disease.
However,
whether
long
length
advantageous
poorly
understood.
Blood,
Journal Year:
2022,
Volume and Issue:
141(16), P. 1909 - 1921
Published: Nov. 8, 2022
BCR::ABL1-negative
myeloproliferative
neoplasms
(MPNs)
are
clonal
diseases
originating
from
a
single
hematopoietic
stem
cell
that
cause
excessive
production
of
mature
blood
cells.
The
3
subtypes,
is,
polycythemia
vera
(PV),
essential
thrombocythemia
(ET),
and
primary
myelofibrosis
(PMF),
diagnosed
according
to
the
World
Health
Organization
(WHO)
international
consensus
classification
(ICC)
criteria.
Acquired
gain-of-function
mutations
in
1
disease
driver
genes
(JAK2,
CALR,
MPL)
causative
events
can
alone
initiate
promote
MPN
without
requiring
additional
cooperating
mutations.
JAK2-p.V617F
is
present
>95%
PV
patients,
also
about
half
patients
with
ET
or
PMF.
PMF
caused
by
CALR
MPL.
In
∼10%
those
referred
as
being
"triple
negative,"
none
known
gene
be
detected.
common
theme
between
triple-negative
Janus
kinase-signal
transducer
activator
transcription
(JAK/STAT)
signaling
pathway
constitutively
activated.
We
review
recent
advances
our
understanding
early
after
acquisition
mutation.
limiting
factor
determines
frequency
at
which
develops
long
latency
not
mutations,
but
rather
expansion
clone.
Factors
control
conversion
hematopoiesis
include
inherited
predisposition,
presence
inflammation.
full
extent
knowledge
mutational
landscape
individual
now
increasingly
used
predict
outcome
chose
optimal
therapy.
Blood,
Journal Year:
2023,
Volume and Issue:
141(16), P. 1934 - 1942
Published: Feb. 6, 2023
Polycythemia
vera
(PV)
is
a
hematopoietic
stem
cell
neoplasm
defined
by
activating
somatic
mutations
in
the
JAK2
gene
and
characterized
clinically
overproduction
of
red
blood
cells,
platelets,
neutrophils;
significant
burden
disease-specific
symptoms;
high
rates
vascular
events;
evolution
to
myelofibrosis
phase
or
acute
leukemia.
The
JAK2V617F
variant
allele
frequency
(VAF)
key
determinant
outcomes
PV,
including
thrombosis
myelofibrotic
progression.
Here,
we
critically
review
dynamic
role
mutation
pathogenesis
natural
history
suitability
VAF
as
diagnostic
prognostic
biomarker,
utility
reduction
PV
treatment.
Nature,
Journal Year:
2024,
Volume and Issue:
627(8003), P. 389 - 398
Published: Jan. 22, 2024
Abstract
The
human
blood
system
is
maintained
through
the
differentiation
and
massive
amplification
of
a
limited
number
long-lived
haematopoietic
stem
cells
(HSCs)
1
.
Perturbations
to
this
process
underlie
diverse
diseases,
but
clonal
contributions
haematopoiesis
how
changes
with
age
remain
incompletely
understood.
Although
recent
insights
have
emerged
from
barcoding
studies
in
model
systems
2–5
,
simultaneous
detection
cell
states
phylogenies
natural
barcodes
humans
remains
challenging.
Here
we
introduce
an
improved,
single-cell
lineage-tracing
based
on
deep
naturally
occurring
mitochondrial
DNA
mutations
readout
transcriptional
chromatin
accessibility.
We
use
define
architecture
HSCs
map
physiological
state
output
clones.
uncover
functional
heterogeneity
HSC
clones,
which
stable
over
months
manifests
as
both
differences
total
biases
towards
production
different
mature
types.
also
find
that
diversity
clones
decreases
markedly
age,
leading
oligoclonal
structure
multiple
distinct
expansions.
Our
study
thus
provides
clonally
resolved
cell-state-aware
atlas
at
resolution,
showing
unappreciated
and,
more
broadly,
paving
way
for
refined
dynamics
across
range
tissues
health
disease.
Blood,
Journal Year:
2023,
Volume and Issue:
142(26), P. 2235 - 2246
Published: Nov. 6, 2023
Abstract
Clonal
hematopoiesis
(CH)
is
described
as
the
outsized
contribution
of
expanded
clones
hematopoietic
stem
and
progenitor
cells
(HSPCs)
to
blood
cell
production.
The
prevalence
CH
increases
dramatically
with
age.
can
be
caused
by
somatic
mutations
in
individual
genes
or
gains
and/or
losses
larger
chromosomal
segments.
a
premalignant
state;
detected
are
initiating
for
hematologic
malignancies,
strong
predictor
development
cancers.
Moreover,
associated
nonmalignant
disorders
increased
overall
mortality.
that
drive
clonal
expansion
HSPCs
alter
function
terminally
differentiated
cells,
including
release
elevated
levels
inflammatory
cytokines.
These
cytokines
may
then
contribute
broad
range
increase
Specific
peripheral
coordination
count
parameters
powerfully
predict
malignancies
mortality
CH.
In
this
review,
we
summarize
current
understanding
nosology
origins.
We
provide
an
overview
available
tools
risk
stratification
discuss
management
strategies
patients
presenting
hematology
clinics.
Nature,
Journal Year:
2023,
Volume and Issue:
620(7974), P. 607 - 614
Published: July 26, 2023
Recent
studies
have
documented
frequent
evolution
of
clones
carrying
common
cancer
mutations
in
apparently
normal
tissues,
which
are
implicated
development1-3.
However,
our
knowledge
is
still
missing
with
regard
to
what
additional
driver
events
take
place
order,
before
one
or
more
these
tissues
ultimately
evolve
cancer.
Here,
using
phylogenetic
analyses
multiple
microdissected
samples
from
both
and
non-cancer
lesions,
we
show
unique
evolutionary
histories
breast
cancers
harbouring
der(1;16),
a
alteration
found
roughly
20%
cancers.
The
approximate
timing
early
was
estimated
the
mutation
rate
measured
epithelial
cells.
In
der(1;16)(+)
cancers,
derivative
chromosome
acquired
puberty
late
adolescence,
followed
by
emergence
ancestor
patient's
30s,
evolved.
Replacing
pre-existing
mammary
epithelium
following
years,
occupied
large
area
within
premenopausal
time
diagnosis.
Evolution
independent
founders
ancestors
common,
contributing
intratumour
heterogeneity.
number
did
not
correlate
histology,
suggesting
role
local
microenvironments
and/or
epigenetic
events.
A
similar
pattern
also
observed
another
case
evolving
an
AKT1-mutated
founder.
Taken
together,
findings
provide
new
insight
into
how
evolves.
Nature Genetics,
Journal Year:
2024,
Volume and Issue:
56(6), P. 1147 - 1155
Published: May 14, 2024
Abstract
Human
aging
is
marked
by
the
emergence
of
a
tapestry
clonal
expansions
in
dividing
tissues,
particularly
evident
blood
as
hematopoiesis
(CH).
CH,
linked
to
cancer
risk
and
aging-related
phenotypes,
often
stems
from
somatic
mutations
set
established
genes.
However,
majority
clones
lack
known
drivers.
Here
we
infer
gene-level
positive
selection
whole
exomes
200,618
individuals
UK
Biobank.
We
identify
17
additional
genes,
ZBTB33
,
ZNF318
ZNF234
SPRED2
SH2B3
SRCAP
SIK3
SRSF1
CHEK2
CCDC115
CCL22
BAX
YLPM1
MYD88
MTA2
MAGEC3
IGLL5
under
at
population
level,
validate
this
pattern
10,837
genomes
single-cell-derived
hematopoietic
colonies.
Clones
with
these
genes
grow
frequency
size
age,
comparable
classical
CH
They
correlate
heightened
infection,
death
hematological
malignancy,
highlighting
significance
process.