CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/da408a6e-f1cc-4856-9d03-cf8640695844
- author
- organization
-
- LUCC: Lund University Cancer Centre
- Targeted therapies in leukemia (research group)
- Translational Genomic and Functional Studies of Leukemia (research group)
- The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy (research group)
- Division of Molecular Medicine and Gene Therapy
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Pathology, Lund
- Hematogenomics (research group)
- publishing date
- 2020-05-26
- 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}}, }