Extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) nucleotides increase the proliferation and engraftment potential of normal human hematopoietic stem cells via the engagement of purinergic receptors (P2Rs). Here, we show that ATP or UTP have strikingly opposite effects on human acute myeloblastic leukemia (AML) cells. Leukemic cells express P2Rs. ATP-stimulated leukemic cells, but not normal CD34+ cells, undergo down-regulation of genes involved in cell proliferation and migration whereas cell cycle inhibitors are up-regulated. Functionally, ATP induced the inhibition of proliferation and accumulation of AML cells, but not of normal cells, in the G0 phase of cell cycle. Exposure to ATP or UTP inhibited AML cell migration in vitro. In vivo, xenotransplant experiments demonstrated that the homing and the engraftment capacity of AML blasts and CD34+CD38- cells to immunodeficient mice bone marrow was significantly inhibited by pre-treatment with nucleotides. P2Rs expression analysis and pharmacological profile suggest that the inhibition of proliferation by ATP was mediated by the down-regulation of the P2X7R, which is upregulated on untreated blasts, while the inhibition of chemotaxis was mainly mediated via P2Y2R and P2Y4R subtypes. Thus, conversely to normal cells, P2Rs signaling inhibits leukemic cells and its pharmacologic modulation may represent a novel therapeutic strategy.
PURINERGIC SIGNALLING INHIBITS HUMAN ACUTE MYELOBLASTIC LEUKEMIA CELL PROLIFERATION, MIGRATION AND ENGRAFTMENT IN IMMUNODEFICIENT MICE.
GULINELLI, Sara;DI VIRGILIO, Francesco;FERRARI, Davide;
2012
Abstract
Extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) nucleotides increase the proliferation and engraftment potential of normal human hematopoietic stem cells via the engagement of purinergic receptors (P2Rs). Here, we show that ATP or UTP have strikingly opposite effects on human acute myeloblastic leukemia (AML) cells. Leukemic cells express P2Rs. ATP-stimulated leukemic cells, but not normal CD34+ cells, undergo down-regulation of genes involved in cell proliferation and migration whereas cell cycle inhibitors are up-regulated. Functionally, ATP induced the inhibition of proliferation and accumulation of AML cells, but not of normal cells, in the G0 phase of cell cycle. Exposure to ATP or UTP inhibited AML cell migration in vitro. In vivo, xenotransplant experiments demonstrated that the homing and the engraftment capacity of AML blasts and CD34+CD38- cells to immunodeficient mice bone marrow was significantly inhibited by pre-treatment with nucleotides. P2Rs expression analysis and pharmacological profile suggest that the inhibition of proliferation by ATP was mediated by the down-regulation of the P2X7R, which is upregulated on untreated blasts, while the inhibition of chemotaxis was mainly mediated via P2Y2R and P2Y4R subtypes. Thus, conversely to normal cells, P2Rs signaling inhibits leukemic cells and its pharmacologic modulation may represent a novel therapeutic strategy.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
