New Nature Communications paper Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression
Lorena Arranz, leader of the Stem Cells, Ageing and Cancer group and Deputy Director of CRESCO and Vincent Cuminetti, researcher in her group, are first and last authors of this Nature Communications paper.
The team investigated a cell surface sensor called SUCNR1 (the succinate receptor) and how it affects blood stem cells and acute myeloid leukemia (AML). They found that SUCNR1 acts like a brake on blood stem cell activity and helps prevent leukemia from progressing.
Low succinate receptor levels - worse outcome
Succinate, a normal metabolic molecule, can fuel abnormal blood cell growth in different ways. Giving extra succinate made leukemia progress faster in several mouse models and AML xenografts when SUCNR1 levels were low or undetected. Patients whose AML cells have low SUCNR1 have shorter overall and progression‑free survival.
Removing SUCNR1 in mice expanded the pool of hematopoietic stem and progenitor cells (HSPCs) and increased overall blood production, including more myeloid cells in the bone marrow. SUCNR1‑positive stem cells were less able to repopulate when transplanted, indicating restricted function.
The team found that SUCNR1 activation counteracts the intracellular effects of succinate and keeps HSPCs’ gene programs in a healthy state by controlling two inflammatory proteins, S100A8 and S100A9. When SUCNR1 is lost, S100A8/A9 increase and drive harmful, inflammatory changes in HSPCs. Blocking S100A9 with the drug tasquinimod in mice with no SUCNR1 reduced these harmful effects in the mice, correcting the numbers of HSPCs and blood cell production.
New treatment strategy
Combining S100A9 inhibition with tasquinimod and a SUCNR1 activator produced better outcomes in AML mouse models, suggesting a new treatment strategy worth pursuing towards potential translation in patients. In treated mice, this combination reduced the numbers of leukemia stem cells, the cells of origin of AML, and lowered the abnormal white blood cell counts.
In conclusion, SUCNR1 is an important regulator that restrains blood stem cell activation and prevents inflammatory, leukemia‑promoting changes in HSPCs. Low SUCNR1 removes that restraint and helps AML progress, but the pathway offers druggable targets (S100A9 and SUCNR1) that showed promise in animal, preclinical studies. In the first translational steps for AML patients, the team’s work points to SUCNR1 as both a prognostic marker and a potential therapeutic vulnerability.
Links:
The paper:
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 JE, Arranz L (2026)
Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression
Nat Commun (in press)
DOI 10.1038/s41467-026-68906-2, PubMed 41644523
Lorena Arranz group:
OUH - Stem Cells, Ageing and Cancer
CRESCO homepage:
Centre for Embryology and Healthy Development - CRESCO