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ACUTE MYELOID LEUKEMIA

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

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.

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Fig. 1: CXCR4 pathway activity discriminates human AML patients with a transcriptional signature enriched in DNA damage, oxidative stress and metabolic reprogramming.
Fig. 2: Deletion of Cxcl12 from Prx1 + mesenchymal cells modulate leukemia dynamics in MLL::AF9-driven AML.
Fig. 3: CXCL12 produced by mature osteolineage cells does not affect leukemia dynamics in MLL::AF9-driven AML.
Fig. 4: Sustained deprivation of CXCL12 produced by Prx1-MSCs does not affect LSC homing nor their localization in the bone marrow.
Fig. 5: Deletion of Cxcl12 from mesenchymal stromal cells leads to cell cycle arrest and cell death in LSCs.
Fig. 6: CXCL12 produced by mesenchymal stromal cells protects LSCs from oxidative stress-induced DNA damage and cell death.
Fig. 7: Mesenchymal stromal cells control leukemic cell’s energy metabolism through CXCL12 production.

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Acknowledgements

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.

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ACV performed experiments, analyzed and interpreted the data, and wrote the manuscript. IAC performed experiments, analyzed data, and edited the manuscript. ICA, DO, PSM, JPR, AVZ, LV, MC, PV, EG, FGM, NGC, LPC, LEL-V, SMF, DO, FPl, IA, TJL LB, PRC, and JJR performed experiments and analyzed the data. RZY, APS, and FPr interpreted the data, designed experiments, and edited the manuscript. BS: conceived the study, performed, analyzed, and interpreted the experimental data, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Borja Saez.

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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

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