TY - JOUR
T1 - Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation
AU - Xie, Stephanie Z.
AU - Kaufmann, Kerstin B.
AU - Wang, Weijia
AU - Chan-Seng-Yue, Michelle
AU - Gan, Olga I.
AU - Laurenti, Elisa
AU - Garcia-Prat, Laura
AU - Takayanagi, Shin Ichiro
AU - Ng, Stanley W.K.
AU - Xu, Chang Jiang
AU - Zeng, Andy G.X.
AU - Jin, Liqing
AU - McLeod, Jessica
AU - Wagenblast, Elvin
AU - Mitchell, Amanda
AU - Kennedy, James A.
AU - Liu, Qiang
AU - Boutzen, Héléna
AU - Kleinau, Melissa
AU - Jargstorf, Joseph
AU - Holmes, Gareth
AU - Zhang, Yang
AU - Voisin, Veronique
AU - Bader, Gary D.
AU - Wang, Jean C.Y.
AU - Hannun, Yusuf A.
AU - Luberto, Chiara
AU - Schroeder, Timm
AU - Minden, Mark D.
AU - Dick, John E.
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85127329771
U2 - 10.1158/2643-3230.BCD-20-0155
DO - 10.1158/2643-3230.BCD-20-0155
M3 - Article
C2 - 34238756
AN - SCOPUS:85127329771
SN - 2643-3230
VL - 2
SP - 32
EP - 53
JO - Blood Cancer Discovery
JF - Blood Cancer Discovery
IS - 1
ER -