Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato<sup>+</sup> HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

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Publication Details

Journal
Nature Communications
Published
2026-02-05
DOI
https://doi.org/10.1038/s41467-026-68906-2
Primary Topic
Immune cells in cancer
Type
article
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0.00
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article

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

Marcel Heugel, Manuel Lobo, Vincent Cuminetti, Deo Prakash Pandey et al.
Nature Communications
Immune cells in cancer
article

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

Marcel Heugel, Manuel Lobo, Vincent Cuminetti, Deo Prakash Pandey, Emeline Boët, Alicia Villatoro, Franco Grimolizzi, Joanna Konieczny, Paloma García, Aurora Bernal, Giovanna Giovinazzo, Ruth H. Paulssen, Marc Ferré, Nick van Gastel, H. Taman, Carlos Torroja, Jean-Emmanuel Sarry, Nuria Vilaplana-Lopera, Thomas Vogl, Fátima Sánchez-Cabo, Anders Vik, Caroline A. Heckman, Lorena Arranz
article en

Abstract

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato<sup>+</sup> HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

Nature CommunicationsVol. 17(1)
Oslo University Hospital (NO), University Hospital of North Norway (NO), Inserm (FR), University of Oslo (NO), University of Münster (DE), Spanish National Centre for Cardiovascular Research (ES), Centre de Recherches en Cancérologie de Toulouse (FR), Cell Technology (China) (HK), de Duve Institute (BE), Institute for Molecular Medicine Finland (FI), UiT The Arctic University of Norway (NO), University of Birmingham (GB), UCLouvain (BE)
Openalex Percentile: Top 64%
Immune cells in cancer
DOIOpen Access PDFOpenAlex
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