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The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells

Item Type:Article
Title:The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells
Creators Name:Viñado, A.C. and Calvo, I.A. and Cenzano, I. and Olaverri, D. and Cocera, M. and San Martin-Uriz, P. and Romero, J.P. and Vilas-Zornoza, A. and Vera, L. and Gomez-Cebrian, N. and Puchades-Carrasco, L. and Lisi-Vega, L.E. and Apaolaza, I. and Valera, P. and Guruceaga, E. and Granero-Molto, F. and Ripalda-Cemborain, P. and Luck, T.J. and Bullinger, L. and Planes, F.J. and Rifon, J.J. and Méndez-Ferrer, S. and Yusuf, R.Z. and Pardo-Saganta, A. and Prosper, F. and Saez, B.
Abstract:Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.
Keywords:Acute Myeloid Leukaemia, Cancer Metabolism, Cancer Microenvironment
Source:Leukemia
ISSN:0887-6924
Publisher:Nature Publishing Group
Volume:36
Number:8
Page Range:1969-1979
Date:August 2022
Official Publication:https://doi.org/10.1038/s41375-022-01601-5
PubMed:View item in PubMed

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