The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells
Ana C Viñado # 1 2 , Isabel A Calvo # 1 2 , Itziar Cenzano 1 , Danel Olaverri 3 , Miguel Cocera 1 , Patxi San Martin-Uriz 1 , Juan P Romero 1 , Amaia Vilas-Zornoza 1 , Laura Vera 4 , Nuria Gomez-Cebrian 5 , Leonor Puchades-Carrasco 5 , Livia E Lisi-Vega 6 , Iñigo Apaolaza 3 7 , Pablo Valera 1 , Elisabeth Guruceaga 1 , Froilan Granero-Molto 4 8 9 , Purificacion Ripalda-Cemborain 4 9 , Tamara J Luck 10 11 , Lars Bullinger 10 11 , Francisco J Planes 3 7 , José J Rifon 12 , Simón Méndez-Ferrer 6 , Rushdia Z Yusuf 13 , Ana Pardo-Saganta 14 15 16 , Felipe Prosper 1 2 12 , Borja Saez 17 18
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.
CITATION Leukemia. 2022 Aug;36(8):1969-1979. doi: 10.1038/s41375-022-01601-5. Epub 2022 May 26