Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells
- University of Birmingham, United Kingdom
- UiT The Arctic University of Norway, Norway
- University of Lübeck, Germany
- University Medical Center Groningen, Netherlands
- 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.
Article and author information
Author details
Grigorios Papatzikas
Jan Jacob Schuringa
Funding
Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)
- Nuria Vilaplana-Lopera
- Grigorios Papatzikas
- Alan Cunningham
- Ayşegül 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 Cunningham
Horizon 2020 Framework Programme (H2020-MSCA-ITN-2015-675790)
- Ayşegül 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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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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Glutamine synthetases (GS) are central enzymes essential for the nitrogen metabolism across all domains of life. Consequently, they have been extensively studied for more than half a century. Based on the ATP-dependent ammonium assimilation generating glutamine, GS expression and activity are strictly regulated in all organisms. In the methanogenic archaeon Methanosarcina mazei, it has been shown that the metabolite 2-oxoglutarate (2-OG) directly induces the GS activity. Besides, modulation of the activity by interaction with small proteins (GlnK1 and sP26) has been reported. Here, we show that the strong activation of M. mazei GS (GlnA1) by 2-OG is based on the 2-OG dependent dodecamer assembly of GlnA1 by using mass photometry (MP) and single particle cryo-electron microscopy (cryo-EM) analysis of purified strep-tagged GlnA1. The dodecamer assembly from dimers occurred without any detectable intermediate oligomeric state and was not affected in the presence of GlnK1. The 2.39 Å cryo-EM structure of the dodecameric complex in the presence of 12.5 mM 2-OG demonstrated that 2-OG is binding between two monomers. Thereby, 2-OG appears to induce the dodecameric assembly in a cooperative way. Furthermore, the active site is primed by an allosteric interaction cascade caused by 2-OG-binding towards an adaption of an open active state conformation. In the presence of additional glutamine, strong feedback inhibition of GS activity was observed. Since glutamine dependent disassembly of the dodecamer was excluded by MP, feedback inhibition most likely relies on the binding of glutamine to the catalytic site. Based on our findings, we propose that under nitrogen limitation the induction of M. mazei GS into a catalytically active dodecamer is not affected by GlnK1 and crucially depends on the presence of 2-OG.
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