See article, p. 32.
Inflammatory signaling perturbs hematopoietic stem cell (HSC) differentiation through a process termed emergency hematopoiesis. Whether an equivalent process has a role in regulating leukemia stem cells (LSC) is unclear. Here Xie and colleagues demonstrate that sphingosine-1-phosphate receptor 3 (S1RP3), a receptor for proinflammatory and bioactive lipid sphingosine-1-phosphate (S1P), drives myeloid differentiation in both HSC and LSC. S1RP3 expression is high in CD33+ myeloid cells and low in primitive CD34+ cells. When S1RP3 is upregulated, it promotes myeloid differentiation in synergy with proinflammatory signaling pathways in HSC and LSC. In addition, S1RP3 expression level could be utilized to stratify acute myeloid leukemia (AML) patients into more differentiated and more primitive cases. Moreover, pharmacologic disruption of S1P signaling by the S1P prodrug FTY720 reduces LSC frequency and decreases leukemia burden in vivo. The results suggest that S1RP3 could serve as both a biomarker and...