Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration Open Access

• MSC-derived S100A8 promotes AML progression by activating the PI3K/Akt signaling pathway through TLR4.

• S100A8 deletion in MSCs transiently reduces HSC numbers but enhances long-term hematopoietic regeneration under stress.

The role of 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 mesenchymal stromal cells (MSCs) had dysregulated expression of the inflammatory cytokine S100A8 in AML. Upregulating S100A8 in MSCs increased the proliferation 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. S100A8 binds to the TLR4 receptor on leukemia cells, activating the PI3K/Akt pathway. In addition, removing S100A8 from MSCs caused a temporary decline in hematopoietic stem cells (HSCs) number, but facilitated long-term hematopoietic recovery under stress. Furthermore, S100A8 inhibited MSC differentiating into osteoblasts and reduced the expression of osteopontin, which is required to support HSCs. Our findings highlight the importance of niche inflammation in promoting AML development while impeding hematopoietic regeneration.