Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis, driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSC by activating stress myelopoiesis, such roles in LSC are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator which drives myeloid differentiation and activates inflammatory programs in both HSC and LSC. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across AML patient cohorts, each with distinct phenotypic and clinical properties. S1PR3 was high in LSC and blasts of mature myeloid samples with linkages to chemosensitivity, while S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.J.E.D is supported by funds from the: Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research through funding provided by the Government of Ontario, Canadian Institutes for Health Research grants 130412, 89932, and 154293, International Development Research Centre Ottawa Canada grants 108401 and 109153, Canadian Cancer Society grant 703212, Terry Fox New Frontiers Program Project Grant 1047, University of Toronto’s Medicine by Design initiative with funding from the Canada First Research Excellence Fund, and a Canada Research Chair. E.L. is supported by Wellcome grant 107630/Z/15/Z and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute. C.L. is supported by NIH, NCI grant P01-CA097132. W.W. was supported by the Swiss Initiative in Systems Biology Transition Postdoc fellowship
