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.
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We thank P. Garcia-Olloqui, Z. Blasco, E. Petri, E. Santamaría, G. Abizanda and E. Iglesias for their technical assistance. Thanks to S. Sykes and N. van Gastel for their insights and assistance with experiments and the staff of the flow cytometry core, the genomics lab and the animal facility at CIMA. This work was supported by the Instituto de Salud Carlos III (ISCIII) (PI17/01346 and PI20/00152), co-funded by the ERDF (A way to make Europe); FC-AECC (AIO16163636SAEZ); Gobierno de Navarra (0011-3638-2020-000011 and 0011-3597-2020-000005) co-funded by the ERDF through the Operative Program 2014-2020 of Navarra to BS. PI17/00701, and PI20/01308, CIBERONC (CB16/12/00489); ERA-NET Program EraPERMED (MEET-AML); Gobierno de Navarra (AGATA 0011-1411-2020-000010/0011-1411-2020-000011); Fundación La Caixa (GR-NET NORMAL-HIT HR20-00871); and Cancer Research UK [C355/A26819] and FC AECC and AIRC under the Accelerator Award Program to FP. Cancer Research UK [C61367/A26670], MRC [MR/V005421/1] and NHS Blood and Transplant to SM-F and LEL-V. Gobierno de Navarra predoctoral fellowship to ACV. Marie Curie grant (H2020-MSCA-IF-837491) to IAC. AECC predoctoral fellowship to ICA.
The authors declare no competing interests.
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Viñado, A.C., Calvo, I.A., Cenzano, I. et al. The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells. Leukemia 36, 1969–1979 (2022). https://doi.org/10.1038/s41375-022-01601-5