Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1 [RNA-seq]
Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during aging remain rudimentary. Here we report that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes leukemic cell expansion. Specifically, we show that ADP-D-glycero-b-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to gram-negative bacteria, is uniquely found in the circulation of older individuals and favors the expansion of pre-leukemic hematopoietic stem cells. Mechanistically, ADP-heptose binds its receptor, ALPK1, triggering transcriptional reprogramming that endows pre-leukemic cells with a competitive advantage. Thus, the accumulation of ADP-heptose represents a direct link between aging and expansion of rare pre-leukemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukemia and immune-related conditions. Overall design: mRNA profile of Dnmt3aWT (Dnmt3a+/+;MxCre), Dnmt3aKO (Dnmt3aF/F;MxCre+) and Dnmt3aKO;Alpk1KO murine BM HSPC (LSK) treated with either water (H2O) or ADP-heptose for 90 min.