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
2026-02-05
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.