Abstract
Background
Acute
myeloid
leukemia
(AML)
is
characterized
by
cellular
and
genetic
heterogeneity,
which
correlates
with
clinical
course.
Although
single-cell
RNA
sequencing
(scRNA-seq)
reflect
this
diversity
to
some
extent,
the
low
sample
numbers
in
individual
studies
limit
analytic
potential
of
comparisons
specific
patient
groups.
Results
We
performed
large
scale
integration
published
scRNA-seq
datasets
create
a
unique
transcriptomic
atlas
for
AML
(AML
scAtlas),
totaling
748,679
cells,
from
159
patients
44
healthy
donors
20
different
studies.
This
largest
data
resource
our
knowledge,
publicly
available
at
https://cellxgene.bmh.manchester.ac.uk/AML/.
scAtlas,
allowed
exploration
importance
age
t(8;21)
an
unprecedented
level,
given
in-utero
origin
pediatric
disease.
uncovered
age-associated
gene
regulatory
network
(GRN)
signatures,
we
validated
using
bulk
delineate
distinct
groups
divergent
biological
characteristics.
Furthermore,
additional
multiomic
dataset
(scRNA-seq
scATAC-seq),
created
de-noised
GRN
reflecting
previously
defined
age-related
signatures.
Conclusions
Applying
integrated
analysis
reveal
age-dependent
regulation
t(8;21),
perhaps
immature/fetal
HSC
prenatal
disease
vs
postnatal
origin.
Our
revealed
that
BCLAF1,
particularly
enriched
inferred
origin,
promising
prognostic
indicator.
The
scAtlas
provides
powerful
investigate
molecular
mechanisms
underlying
subtypes.
The Journal of Experimental Medicine,
Journal Year:
2025,
Volume and Issue:
222(6)
Published: March 12, 2025
Leukemia-driving
mutations
are
thought
to
arise
in
hematopoietic
stem
cells
(HSC),
yet
the
natural
history
of
their
spread
is
poorly
understood.
We
genetically
induced
within
endogenous
murine
HSC
and
traced
them
unmanipulated
animals.
In
contrast
associated
with
clonal
hematopoiesis
(such
as
Tet2
deletion),
leukemogenic
KrasG12D
mutation
dramatically
accelerated
contribution
all
lineages.
The
acceleration
was
mediated
by
KrasG12D-expressing
multipotent
progenitors
(MPP)
that
lacked
self-renewal
but
showed
increased
proliferation
aberrant
transcriptome.
deletion
osteopontin,
a
secreted
negative
regulator
stem/progenitor
cells,
delayed
early
expansion
mutant
progenitors.
KrasG12D-carrying
CXCR4-driven
motility
bone
marrow,
blockade
CXCR4
reduced
MPP
vivo.
Finally,
therapeutic
KRASG12D
spared
mature
progeny.
Thus,
transforming
facilitate
own
from
reprogramming
MPP,
creating
preleukemic
state
via
two-component
circuit.
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: April 3, 2025
Cancer
stem
cells
are
essential
for
initiation
and
therapy
resistance
of
many
cancers,
including
acute
myeloid
leukemias
(AML).
Here,
we
apply
functional
genomic
profiling
to
diverse
human
leukemias,
high-risk
MLL-
NUP98-rearranged
specimens,
using
label
tracing
in
vivo.
Human
leukemia
propagation
is
mediated
by
a
rare
quiescent
label-retaining
cell
(LRC)
population
undetectable
current
immunophenotypic
markers.
AML
quiescence
reversible,
preserving
genetic
clonal
competition
epigenetic
inheritance.
LRC
defined
distinct
promoter-centered
chromatin
gene
expression
dynamics
controlled
an
AP-1/ETS
transcription
factor
network,
where
JUN
necessary
sufficient
associated
with
persistence
chemotherapy
patients.
This
enables
prospective
isolation
manipulation
immunophenotypically-varied
cells,
establishing
the
functions
plasticity
development
resistance.
These
findings
offer
insights
into
design
therapeutic
strategies
their
clinical
identification
control.
Cell,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 1, 2025
During
cellular
differentiation,
enhancers
transform
overlapping
gradients
of
transcription
factors
(TFs)
to
highly
specific
gene
expression
patterns.
However,
the
vast
complexity
regulatory
DNA
impedes
identification
underlying
cis-regulatory
rules.
Here,
we
characterized
64,400
fully
synthetic
sequences
bottom-up
dissect
design
principles
cell-state-specific
in
context
differentiation
blood
stem
cells
seven
myeloid
lineages.
Focusing
on
binding
sites
for
38
TFs
and
their
pairwise
interactions,
found
that
identical
displayed
both
repressive
activating
function
as
a
consequence
cell
state,
site
combinatorics,
or
simply
predicted
occupancy
TF
an
enhancer.
Surprisingly,
combinations
frequently
neutralized
one
another
gained
function.
These
negative
synergies
convert
quantitative
imbalances
into
binary
activity
We
exploit
this
principle
automatically
create
with
specificity
user-defined
hematopoietic
progenitor
states
from
scratch.
Abstract
Background
Acute
myeloid
leukemia
(AML)
is
characterized
by
cellular
and
genetic
heterogeneity,
which
correlates
with
clinical
course.
Although
single-cell
RNA
sequencing
(scRNA-seq)
reflect
this
diversity
to
some
extent,
the
low
sample
numbers
in
individual
studies
limit
analytic
potential
of
comparisons
specific
patient
groups.
Results
We
performed
large
scale
integration
published
scRNA-seq
datasets
create
a
unique
transcriptomic
atlas
for
AML
(AML
scAtlas),
totaling
748,679
cells,
from
159
patients
44
healthy
donors
20
different
studies.
This
largest
data
resource
our
knowledge,
publicly
available
at
https://cellxgene.bmh.manchester.ac.uk/AML/.
scAtlas,
allowed
exploration
importance
age
t(8;21)
an
unprecedented
level,
given
in-utero
origin
pediatric
disease.
uncovered
age-associated
gene
regulatory
network
(GRN)
signatures,
we
validated
using
bulk
delineate
distinct
groups
divergent
biological
characteristics.
Furthermore,
additional
multiomic
dataset
(scRNA-seq
scATAC-seq),
created
de-noised
GRN
reflecting
previously
defined
age-related
signatures.
Conclusions
Applying
integrated
analysis
reveal
age-dependent
regulation
t(8;21),
perhaps
immature/fetal
HSC
prenatal
disease
vs
postnatal
origin.
Our
revealed
that
BCLAF1,
particularly
enriched
inferred
origin,
promising
prognostic
indicator.
The
scAtlas
provides
powerful
investigate
molecular
mechanisms
underlying
subtypes.
