Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

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

doi:10.1038/s41467-026-68906-2

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

Vincent Cuminetti
, Emeline Boet
, Marcel Heugel
, Joanna Konieczny
, Aurora Bernal
, Manuel J. Gomez
, Franco Grimolizzi
, Nuria Vilaplana-Lopera
, Marc Ferré
, Alicia Villatoro
, Deo P. Pandey
, Carlos Torroja
, Hagar Taman
, Ruth H. Paulssen
, Thomas Vogl
, Caroline A. Heckman
, Anders Vik
, Giovanna Giovinazzo
, Nick van Gastel
, Paloma García

Fátima Sánchez-Cabo, Jean-Emmanuel Sarry, Lorena Arranz^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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⁺ 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.

Original language	English
Article number	2403
Number of pages	23
Journal	Nature Communications
Volume	17
Issue number	1
Early online date	5 Feb 2026
DOIs	https://doi.org/10.1038/s41467-026-68906-2
Publication status	Published - 12 Mar 2026

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10.1038/s41467-026-68906-2Licence: Creative Commons: Attribution (CC BY)

CuminettiV2026SuccinateFinal published version, 3 MBLicence: Creative Commons: Attribution (CC BY)

HWB-NMR: a national resource for biomolecular research
Tennant, D. (Co-Investigator), Young, S. (Co-Investigator), Lavery, G. (Co-Investigator), Peet, A. (Co-Investigator), Ludwig, C. (Co-Investigator), Futterer, K. (Co-Investigator), Guenther, U. (Co-Investigator), Henderson, I. (Co-Investigator), Willcox, B. (Co-Investigator), Adams, D. (Co-Investigator), Carlomagno, T. (Principal Investigator), Adams, D. (Co-Investigator), Adams, D. (Co-Investigator), Adams, D. (Co-Investigator), Adams, D. (Co-Investigator), Adams, D. (Co-Investigator), Adams, D. (Co-Investigator) & Adams, D. (Co-Investigator)
The Wellcome Trust
25/09/17 → 25/09/24
Project: Research

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Cuminetti, V., Boet, E., Heugel, M., Konieczny, J., Bernal, A., Gomez, M. J., Grimolizzi, F., Vilaplana-Lopera, N., Ferré, M., Villatoro, A., Pandey, D. P., Torroja, C., Taman, H., Paulssen, R. H., Vogl, T., Heckman, C. A., Vik, A., Giovinazzo, G., van Gastel, N., ... Arranz, L. (2026). Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression. Nature Communications, 17(1), Article 2403. https://doi.org/10.1038/s41467-026-68906-2

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title = "Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression",

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+ 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.",

author = "Vincent Cuminetti and Emeline Boet and Marcel Heugel and Joanna Konieczny and Aurora Bernal and Gomez, \{Manuel J.\} and Franco Grimolizzi and Nuria Vilaplana-Lopera and Marc Ferr{\'e} and Alicia Villatoro and Pandey, \{Deo P.\} and Carlos Torroja and Hagar Taman and Paulssen, \{Ruth H.\} and Thomas Vogl and Heckman, \{Caroline A.\} and Anders Vik and Giovanna Giovinazzo and \{van Gastel\}, Nick and Paloma Garc{\'i}a and F{\'a}tima S{\'a}nchez-Cabo and Jean-Emmanuel Sarry and Lorena Arranz",

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month = mar,

day = "12",

doi = "10.1038/s41467-026-68906-2",

language = "English",

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Cuminetti, V, Boet, E, Heugel, M, Konieczny, J, Bernal, A, Gomez, MJ, Grimolizzi, F, Vilaplana-Lopera, N, Ferré, M, Villatoro, A, Pandey, DP, Torroja, C, Taman, H, Paulssen, RH, Vogl, T, Heckman, CA, Vik, A, Giovinazzo, G, van Gastel, N, García, P, Sánchez-Cabo, F, Sarry, J-E & Arranz, L 2026, 'Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression', Nature Communications, vol. 17, no. 1, 2403. https://doi.org/10.1038/s41467-026-68906-2

TY - JOUR

T1 - Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

AU - Cuminetti, Vincent

AU - Boet, Emeline

AU - Heugel, Marcel

AU - Konieczny, Joanna

AU - Bernal, Aurora

AU - Gomez, Manuel J.

AU - Grimolizzi, Franco

AU - Vilaplana-Lopera, Nuria

AU - Ferré, Marc

AU - Villatoro, Alicia

AU - Pandey, Deo P.

AU - Torroja, Carlos

AU - Taman, Hagar

AU - Paulssen, Ruth H.

AU - Vogl, Thomas

AU - Heckman, Caroline A.

AU - Vik, Anders

AU - Giovinazzo, Giovanna

AU - van Gastel, Nick

AU - García, Paloma

AU - Sánchez-Cabo, Fátima

AU - Sarry, Jean-Emmanuel

AU - Arranz, Lorena

PY - 2026/3/12

Y1 - 2026/3/12

N2 - 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+ 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.

AB - 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+ 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.

U2 - 10.1038/s41467-026-68906-2

DO - 10.1038/s41467-026-68906-2

M3 - Article

SN - 2041-1723

VL - 17

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2403

ER -

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

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