Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

  1. Nuria Vilaplana-Lopera
  2. Vincent Cuminetti
  3. Ruba Almaghrabi
  4. Grigorios Papatzikas
  5. Ashok Kumar Rout
  6. Mark Jeeves
  7. Elena González
  8. Yara Alyahyawi
  9. Alan Cunnigham
  10. Ayşegüll Erdem
  11. Frank Schnütgen
  12. Manoj Raghavan
  13. Sandeep Potluri
  14. Jean-Baptiste Cazier
  15. Jan Jacob Schuringa
  16. Michelle AC Reed
  17. Lorena Arranz
  18. Ulrich Günther
  19. Paloma Garcia  Is a corresponding author
  1. University of Birmingham, United Kingdom
  2. UiT The Arctic University of Norway, Norway
  3. University of Lübeck, Germany
  4. University Medical Center Groningen, Netherlands
  5. University Hospital Frankfurt, Germany

Abstract

Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.

Data availability

RNA-seq data has been deposited in GEO under accession number GSE163478.All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.Information about AML patient samples obtained from Martini Hospital (UMCG) (Netherlands) and University Hospital Birmingham NHS Foundation Trust, University of Birmingham (UK) have been provided in supplementary Table 1.Source of mice used can be found in Material and methods.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Nuria Vilaplana-Lopera

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Vincent Cuminetti

    Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8396-710X
  3. Ruba Almaghrabi

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Grigorios Papatzikas

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0163-4174
  5. Ashok Kumar Rout

    Institute of Chemistry and Metabolomics, University of Lübeck, Lubeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark Jeeves

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9736-0990
  7. Elena González

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Yara Alyahyawi

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Alan Cunnigham

    Department of Experimental Hematology, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Ayşegüll Erdem

    Department of Experimental Hematology, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Frank Schnütgen

    Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Manoj Raghavan

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Sandeep Potluri

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Jean-Baptiste Cazier

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Jan Jacob Schuringa

    Department of Experimental Hematology, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8452-8555
  16. Michelle AC Reed

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Lorena Arranz

    Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5896-4238
  18. Ulrich Günther

    Institute of Chemistry and Metabolomics, University of Lübeck, Lubeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Paloma Garcia

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    For correspondence
    p.garcia@bham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5582-8575

Funding

Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)

  • Nuria Vilaplana-Lopera
  • Grigorios Papatzikas
  • Alan Cunnigham
  • Ayşegüll Erdem

European Commission (HaemMetabolome [EC-675790])

  • Jean-Baptiste Cazier

European Commission (HaemMetabolome [EC-675790])

  • Jan Jacob Schuringa

European Commission (HaemMetabolome [EC-675790])

  • Ulrich Günther

European Commission (HaemMetabolome [EC-675790])

  • Paloma Garcia

European Commission (HaemMetabolome [EC-675790)

  • Frank Schnütgen
  • Jean-Baptiste Cazier
  • Jan Jacob Schuringa
  • Ulrich Günther
  • Paloma Garcia

Deutsche Forschungsgemeinschaft (SFB815,TP A10)

  • Frank Schnütgen

Wellcome Trust (208400/Z/17/Z)

  • Ulrich Günther

Helse Nord RHF (2014/5668)

  • Lorena Arranz

University of Birmingham (67262-DIF Post-Covid Support Fund)

  • Paloma Garcia

Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)

  • Grigorios Papatzikas

Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)

  • Alan Cunnigham

Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)

  • Ayşegüll Erdem

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were conducted with the ethical approval of the Norwegian Food and Safety Authority under project number 19472, with a particular focus on reduction and refinement. Animals were housed under specific opportunistic and pathogen free environment at the Animal Facility of the University of Oslo, Norway. The animals were euthanized by CO2 and absence of reflexes was confirmed before necropsy.

Human subjects: AML and PBMC primary specimens' procedures were obtained in accordance with the Declaration of Helsinki at the University Medical Center Groningen, approved by the UMCG Medical Ethical Committee or at the University Hospital Birmingham NHS Foundation Trust, approved by the West Midlands - Solihull Research Ethics Committee (10/H1206//58).

Copyright

© 2022, Vilaplana-Lopera et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nuria Vilaplana-Lopera
  2. Vincent Cuminetti
  3. Ruba Almaghrabi
  4. Grigorios Papatzikas
  5. Ashok Kumar Rout
  6. Mark Jeeves
  7. Elena González
  8. Yara Alyahyawi
  9. Alan Cunnigham
  10. Ayşegüll Erdem
  11. Frank Schnütgen
  12. Manoj Raghavan
  13. Sandeep Potluri
  14. Jean-Baptiste Cazier
  15. Jan Jacob Schuringa
  16. Michelle AC Reed
  17. Lorena Arranz
  18. Ulrich Günther
  19. Paloma Garcia
(2022)
Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells
eLife 11:e75908.
https://doi.org/10.7554/eLife.75908

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https://doi.org/10.7554/eLife.75908

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