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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 36, pages 1969–1979 (2022)Cite this article

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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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Author notes

  1. These authors contributed equally: Ana C. Viñado, Isabel A. Calvo.

  2. These authors jointly supervised this work: Rushdia Z. Yusuf, Ana Pardo-Saganta, Felipe Prosper, Borja Saez.

Authors and Affiliations

  1. Hematology-Oncology Program, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008, Pamplona, Spain

    Ana C. Viñado, Isabel A. Calvo, Itziar Cenzano, Miguel Cocera, Patxi San Martin-Uriz, Juan P. Romero, Amaia Vilas-Zornoza, Pablo Valera, Elisabeth Guruceaga, Felipe Prosper & Borja Saez

  2. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain

    Ana C. Viñado, Isabel A. Calvo, Felipe Prosper & Borja Saez

  3. Tecnun Universidad de Navarra, School of Engineering, 20018, San Sebastian, Spain

    Danel Olaverri, Iñigo Apaolaza & Francisco J. Planes

  4. Regenerative Medicine Program, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008, Pamplona, Spain

    Laura Vera, Froilan Granero-Molto & Purificacion Ripalda-Cemborain

  5. Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe, 46026, Valencia, Spain

    Nuria Gomez-Cebrian & Leonor Puchades-Carrasco

  6. Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, and NHS Blood and Transplant, Cambridge, CB2 0AW, UK

    Livia E. Lisi-Vega & Simón Méndez-Ferrer

  7. Universidad de Navarra, Centro de Ingeniería Biomédica and DATAI Instituto de Ciencia de los Datos e Inteligencia Artificial, 31008, Pamplona, Spain

    Iñigo Apaolaza & Francisco J. Planes

  8. Cell Therapy Area, Clínica Universidad de Navarra, 31008, Pamplona, Spain

    Froilan Granero-Molto

  9. Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, 31008, Pamplona, Spain

    Froilan Granero-Molto & Purificacion Ripalda-Cemborain

  10. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany

    Tamara J. Luck & Lars Bullinger

  11. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Tamara J. Luck & Lars Bullinger

  12. Department of Hematology, Cell Therapy and Center of Cancer of the University of Navarra, Clínica Universidad de Navarra (CCUN), 31008, Pamplona, Spain

    José J. Rifon & Felipe Prosper

  13. Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA

    Rushdia Z. Yusuf

  14. Institute for Lung Health (ILH), Justus Liebig University Giessen, Giessen, 35392, Germany

    Ana Pardo-Saganta

  15. Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 35392, Germany

    Ana Pardo-Saganta

  16. German Center for Lung Research (DZL), Giessen, 35392, Germany

    Ana Pardo-Saganta

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  1. Ana C. Viñado
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Contributions

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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