Preprints

The role of microenvironmental inflammation in the regulation of acute myeloid leukemia (AML) and stressed hematopoiesis is significant, though the molecular mechanisms are not fully understood. Here, we found that MSCs in a leukemic microenvironment had dysregulated expression of the inflammatory cytokine S100A8. Upregulating S100A8 in MSCs increased the proliferation and chemoresistance of AML cells in vitro. In contrast, removing S100A8 from MSCs in the murine MLL-AF9 AML model resulted in longer survival and less infiltration of leukemia cells and leukemic stem cells (LSCs). S100A8 binds to the TLR4 receptor on leukemia cells, which activates the PI3K/Akt pathway. In addition, removing S100A8 from MSCs causes a temporary increase in their quantity, followed by a decline in hematopoietic stem cells (HSCs) in mice exposed to stressful environments. Furthermore, the absence of S100A8 alters the properties of MSCs, impairing their ability to differentiate into osteoblasts and decreasing the expression of osteopontin, which is required to support HSCs. Our findings highlight the importance of MSC-derived S100A8 in promoting the maintenance of LSCs while impeding the maintenance of HSCs, providing new insights into the potential for the management of AML and hematopoietic regeneration.