CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia.
CRISPR
CXCL12
CXCR4
CXCR4 signaling
ROS
acute myeloid leukemia
differentiation
leukemia stem cell
oxidative stress
screen
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 05 2020
26 05 2020
Historique:
received:
25
10
2019
revised:
28
02
2020
accepted:
04
05
2020
entrez:
28
5
2020
pubmed:
28
5
2020
medline:
22
5
2021
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.
Identifiants
pubmed: 32460032
pii: S2211-1247(20)30637-9
doi: 10.1016/j.celrep.2020.107684
pmc: PMC8109054
mid: NIHMS1693424
pii:
doi:
Substances chimiques
CXCL12 protein, human
0
CXCR4 protein, human
0
Chemokine CXCL12
0
MLL-AF9 fusion protein, mouse
0
Oncogene Proteins, Fusion
0
Reactive Oxygen Species
0
Receptors, CXCR4
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
107684Subventions
Organisme : NCI NIH HHS
ID : R01 CA172447
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248794
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 The authors declare no competing interests.
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