Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression

TL;DR

The Succinate receptor 1 (Sucnr1) limits blood cell formation and slows AML progression by controlling S100A9, offering new therapeutic possibilities for AML patients.

Contribution

This study reveals that Sucnr1 restricts hematopoiesis and AML progression via S100A9 regulation, identifying a novel therapeutic target.

Findings

Low SUCNR1 levels correlate with poor survival in AML patients.

Sucnr1 deletion expands hematopoietic stem and progenitor cells.

Blocking S100A9 rescues defects in Sucnr1-deficient mice and shows therapeutic potential in AML.

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.

Succinate metabolism is reported to be involved in acute myeloid leukemia (AML) tumorigenesis. Here, the authors demonstrate that succinate receptor 1 (Sucnr1) restricts hematopoiesis via regulation of S100A9, counterbalancing the Sucnr1-independent tumorigenic effect of succinate in AML.

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