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

Abstract

The role of inflammation in regulating acute myeloid leukemia (AML) and stressed hematopoiesis is significant, although 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 Toll-like receptor 4 on leukemia cells, activating the PI3K/Akt pathway. In addition, removing S100A8 from MSCs caused a temporary decline in hematopoietic stem cell (HSCs) numbers, but facilitated long-term hematopoietic recovery under stress. Furthermore, S100A8 inhibited MSC differentiation into osteoblasts and reduced the expression of osteopontin, which is required for supporting HSCs. Our findings highlight the importance of niche inflammation in promoting AML development while impeding hematopoietic regeneration.