Expression data from untreated and ATP treated AML blasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30903 | GEO | 2012/02/25
SECONDARY ACCESSION(S): PRJNA144221
REPOSITORIES: GEO
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Project description:In the present study, we investigated whether, and to what extent, P2Rs and their ligands are involved in the regulation of AML cells. Our findings show that AML blasts express several receptors belonging to the P2X and P2Y family. Although different samples respond differently to ATP and UTP stimulation (reflecting the variability intrinsic to the group of acute myeloid leukemias), all the tested samples appear to be responsive to purinergic signalling, as demonstrated by intracellular calcium mobilization. GEP analysis demonstrated that ATP induced the expression of cell cycle inhibitors and negative modulators of cell motility, such as inhibitors of GTPase activity. On the contrary, ATP inhibits the expression cell-cycle related genes (cyclins and CDKs), activators of cell motility (Rho GTPases regulators, matrix degradation enzyme and cytoskeleton proteins) and adhesion molecules involved in homing and engraftment. Blast cells obtained from 12 AML patients (3 M0/M1; 3 M2; 3 M4; and 3 M5) were cultured for 24 h with or without 1 mM ATP. Total RNA from 106 ATP-treated and untreated cells was extracted to study variation of gene expression profile induced by ATP treatment in leukemic cells.
2012-02-25 | E-GEOD-30903 | biostudies-arrayexpress
Project description:Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and non-peptide molecules. Extracellular nucleotides and their cognate P2 receptors are emerging as key-factors of inflammation and related chemotactic responses. In this study, we investigated the activity of extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) on CXCL12-stimulated CD34+ HSC chemotaxis. In vitro, UTP significantly improved HSC migration, inhibited cell membrane CXCR4 down-regulation of migrating CD34+ cells and increased cell adhesion to fibronectin. In vivo, pre-incubation with UTP significantly enhanced the BM homing efficiency of human CD34+ cells in immunodeficient mice. Pertussis toxin blocked CXCL12- and UTP-dependent chemotactic responses, suggesting that G-protein alpha-subunits (Gαi) may provide a converging signal for CXCR4- and P2Y-activated transduction pathways. In addition, gene expression profiling of UTP-treated CD34+ cells and in vitro inhibition assays demonstrated that Rho guanosine 5’-triphosphatases (GTPase) Rac2 and downstream effectors Rho GTPase–activated kinases 1 and 2 (ROCK1/2) are involved in UTP-promoted/CXCL12-dependent HSC migration. Our data suggest that UTP may physiologically modulate the migration of HSCs and their homing to the BM, in concert with CXCL12, via the activation of converging signaling pathways between CXCR4 and P2Y receptors, involving Gαi proteins and RhoGTPases. Keywords: treatment comparison
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Project description:Purinergic P2 receptors are critical regulators of several functions within the vascular system, including platelet aggregation, vascular inflammation and vascular tone. A role for ATP release and P2Y receptors in angiogenesis has been implicated, however, the involvement of purinergic signalling in endothelial sprouting and vascular growth remains poorly understood. Here, we demonstrate that blood vessel growth is controlled by P2Y2 receptors. Inhibition of P2Y2 using a selective antagonist or modulation of P2Y2 receptor expression significantly influenced sprouting and vascular tube formation. Mechanistically, overexpression of P2Y2 in endothelial cells resulted in increased expression of the pro-angiogenic molecules CXCR4, CD34 and angiopoietin-2, while expression of Tie2 and VEGFR-2 decreased. Interestingly, elevated P2Y2 expression caused constitutive phosphorylation of ERK1/2 and VEGFR-2. However, stimulation of cells with the P2Y2 agonist UTP did not influence sprouting unless P2Y2 was constitutively expressed, indicating that enhanced receptor expression, and not activation, is the primary trigger for angiogenesis. Our data suggest that P2Y2 receptors have an essential function in angiogenesis through cross-talk of P2Y2 and VEGFR-2 and that P2Y2 may represent a therapeutic target to regulate blood vessel growth.
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2013-04-11 | E-GEOD-14566 | biostudies-arrayexpress
Project description:Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and non-peptide molecules. Extracellular nucleotides and their cognate P2 receptors are emerging as key-factors of inflammation and related chemotactic responses. In this study, we investigated the activity of extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) on CXCL12-stimulated CD34+ HSC chemotaxis. In vitro, UTP significantly improved HSC migration, inhibited cell membrane CXCR4 down-regulation of migrating CD34+ cells and increased cell adhesion to fibronectin. In vivo, pre-incubation with UTP significantly enhanced the BM homing efficiency of human CD34+ cells in immunodeficient mice. Pertussis toxin blocked CXCL12- and UTP-dependent chemotactic responses, suggesting that G-protein alpha-subunits (Gαi) may provide a converging signal for CXCR4- and P2Y-activated transduction pathways. In addition, gene expression profiling of UTP-treated CD34+ cells and in vitro inhibition assays demonstrated that Rho guanosine 5â-triphosphatases (GTPase) Rac2 and downstream effectors Rho GTPaseâactivated kinases 1 and 2 (ROCK1/2) are involved in UTP-promoted/CXCL12-dependent HSC migration. Our data suggest that UTP may physiologically modulate the migration of HSCs and their homing to the BM, in concert with CXCL12, via the activation of converging signaling pathways between CXCR4 and P2Y receptors, involving Gαi proteins and RhoGTPases. Experiment Overall Design: Highly purified CD34+ cells from 6 healthy donors were seeded at 1000000 cells/ml in serum free medium (EX vivo 15) w/o cytokines and treated with 10 mM UTP, 150ng/ml CXCL12, or 10 mM UTP plus 150ng/ml CXCL12 respectively for 24 hours. As a control, CD34+ untreated cells were maintained in the same culture conditions at the same time.
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Project description:Nucleotides triphosphates are extracellular messengers binding to specific plasma membrane receptors (P2Rs) that modulate responses as different as proliferation, differentiation, migration or cell death on several cell types including hematopoietic stem cells. Little and controversial information is available on the role of extracellular nucleotides in human mesenchimal stem cells (hMSCs). In this study, we assessed whether P2Rs are expressed and functional in bone marrow-derived hMSCs. Our results demonstrated, at the mRNA and protein level, the expression of all P2X and P2Y receptor subtypes identified so far. P2R activation by their natural ligands adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced in hMSCs, intracellular Ca2+ concentration changes, plasma membrane depolarization and permeabilization. hMSCs were resistant to the cytotoxic effects of high dose ATP despite the expression of permeabilizing P2Rs as demonstrated by the lack of morphological changes, significant release of intracellular markers of cell death or modification of the mitochondrial network. Gene expression profiling revealed the down-regulation of cell proliferation genes whereas genes involved in cell migration and cytokine production were strongly up-regulated by ATP. Functional studies confirmed the inhibitory activity of ATP on proliferation of hMSCs and clonogenic progenitors. Moreover, ATP exerted a chemotactic effect on hMSCs and increased their migration in response to the chemokine CXCL12. Finally, whereas ATP did not affect T-cell inhibitory activity of hMSCs, the nucleotide increased the production of pro-inflammatory cytokines by hMSCs. Thus, our data show that purinergic signaling modulates hMSC functions and point to a role for extracellular nucleotides on hMSCs biology.
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