Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: 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
Institutions: Oslo University Hospital, University of Oslo, UiT The Arctic University of Norway, Inserm, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Spanish National Centre for Cardiovascular Research, University of Birmingham, University of Münster, University of Helsinki, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, University Hospital of North Norway, de Duve Institute, UCLouvain
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7128034224