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CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia

Ramakrishnan, Ramprasad LU ; Peña-Martínez, Pablo LU ; Agarwal, Puneet ; Rodriguez-Zabala, Maria LU ; Chapellier, Marion LU ; Högberg, Carl LU ; Eriksson, Mia LU ; Yudovich, David LU ; Shah, Mansi and Ehinger, Mats LU , et al. (2020) In Cell Reports 31(8).
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute myeloid leukemia, CRISPR, CXCL12, CXCR4, CXCR4 signaling, differentiation, leukemia stem cell, oxidative stress, ROS, screen
in
Cell Reports
volume
31
issue
8
article number
107684
publisher
Cell Press
external identifiers
  • scopus:85085286993
  • pmid:32460032
ISSN
2211-1247
DOI
10.1016/j.celrep.2020.107684
language
English
LU publication?
yes
id
da408a6e-f1cc-4856-9d03-cf8640695844
date added to LUP
2020-06-16 11:28:57
date last changed
2024-04-03 08:08:25
@article{da408a6e-f1cc-4856-9d03-cf8640695844,
  abstract     = {{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.}},
  author       = {{Ramakrishnan, Ramprasad and Peña-Martínez, Pablo and Agarwal, Puneet and Rodriguez-Zabala, Maria and Chapellier, Marion and Högberg, Carl and Eriksson, Mia and Yudovich, David and Shah, Mansi and Ehinger, Mats and Nilsson, Björn and Larsson, Jonas and Hagström-Andersson, Anna and Ebert, Benjamin L. and Bhatia, Ravi and Järås, Marcus}},
  issn         = {{2211-1247}},
  keywords     = {{acute myeloid leukemia; CRISPR; CXCL12; CXCR4; CXCR4 signaling; differentiation; leukemia stem cell; oxidative stress; ROS; screen}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{8}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2020.107684}},
  doi          = {{10.1016/j.celrep.2020.107684}},
  volume       = {{31}},
  year         = {{2020}},
}