American Association for Cancer Research
26433230bcd200155-sup-250667_2_supp_6713473_qjlbkb.avi (18.74 MB)

Supplementary Data from Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation

Download (18.74 MB)
posted on 2023-04-04, 00:40 authored by Stephanie Z. Xie, Kerstin B. Kaufmann, Weijia Wang, Michelle Chan-Seng-Yue, Olga I. Gan, Elisa Laurenti, Laura Garcia-Prat, Shin-ichiro Takayanagi, Stanley W.K. Ng, ChangJiang Xu, Andy G.X. Zeng, Liqing Jin, Jessica McLeod, Elvin Wagenblast, Amanda Mitchell, James A. Kennedy, Qiang Liu, Héléna Boutzen, Melissa Kleinau, Joseph Jargstorf, Gareth Holmes, Yang Zhang, Veronique Voisin, Gary D. Bader, Jean C.Y. Wang, Yusuf A. Hannun, Chiara Luberto, Timm Schroeder, Mark D. Minden, John E. Dick

Supplemental Movie


Canadian Institutes for Health Research

International Development Research Centre Ottawa Canada

Canadian Cancer Society

Terry Fox New Frontiers Program Project Grant






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 HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas 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. S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.See related commentary by Yang et al., p. 3.This article is highlighted in the In This Issue feature, p. 1