Human Gene Set: XIE_LT_HSC_S1PR3_OE_UP

Standard name XIE_LT_HSC_S1PR3_OE_UP
Systematic name M41754
Brief description Genes upregulated in long-term hematopoietic stem cells (CD34+,CD38_,CD45RA_,CD90+,CD49f+) upon overexpression of Sphingosine-1-Phosphate Receptor 3 (S1PR3)
Full description or abstract 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.
Significance: 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.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 33458693   Authors: Xie SZ,Kaufmann KB,Wang W,Chan-Seng-Yue M,Gan OI,Laurenti E,Garcia-Prat L,Takayanagi SI,Ng SWK,Xu C,Zeng AGX,Jin L,McLeod J,Wagenblast E,Mitchell A,Kennedy JA,Liu Q,Boutzen H,Kleinau M,Jargstorf J,Holmes G,Zhang Y,Voisin V,Bader GD,Wang JCY,Hannun YA,Luberto C,Schroeder T,Minden MD,Dick JE
Exact source Supplemental Table 3: LT-HSC DEGs. Differentially expressed genes with S1PR3 overexpression in LT-HSC and ST-HSC (q=0.05, fold change >1)
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