Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells.
Animals
Cell Differentiation
Cell Line
Chromatin
/ metabolism
Core Binding Factor Alpha 2 Subunit
/ antagonists & inhibitors
Gene Expression Regulation
Genetic Heterogeneity
Hematopoietic Stem Cells
/ cytology
Humans
Induced Pluripotent Stem Cells
/ cytology
Leukemia, Myeloid, Acute
/ metabolism
Markov Chains
Mice
Mice, Inbred NOD
Mice, SCID
Phenotype
RNA Interference
RNA, Small Interfering
/ metabolism
RNA-Seq
Single-Cell Analysis
AML
LSC gene signature
Leukemia stem cells
RUNX1
iLSCs
iPSCs
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
02 06 2020
02 06 2020
Historique:
received:
29
01
2020
revised:
12
03
2020
accepted:
04
05
2020
entrez:
4
6
2020
pubmed:
4
6
2020
medline:
4
5
2021
Statut:
ppublish
Résumé
Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs.
Identifiants
pubmed: 32492433
pii: S2211-1247(20)30641-0
doi: 10.1016/j.celrep.2020.107688
pmc: PMC7786450
mid: NIHMS1604610
pii:
doi:
Substances chimiques
Chromatin
0
Core Binding Factor Alpha 2 Subunit
0
RNA, Small Interfering
0
RUNX1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107688Subventions
Organisme : NCI NIH HHS
ID : R01 CA166835
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145283
Pays : United States
Organisme : NCI NIH HHS
ID : DP2 CA239065
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007739
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121570
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA225231
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132071
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA186702
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101989
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135564
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193842
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA240139
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests E.P.P. has received honoraria from Celgene and Merck and research support from Incyte. M.G.K. has received consultant fees from Acent Therapeutics and research support from 28-7. These disclosures are not directly related to the present study.