Purinergic signaling inhibits human acute myeloblastic leukemia cell proliferation, migration, and engraftment in immunodeficient mice

• Published in: Blood Vol. 119; no. 1; pp. 217 - 226
• Main Authors: Salvestrini, Valentina, Zini, Roberta, Rossi, Lara, Gulinelli, Sara, Manfredini, Rossella, Bianchi, Elisa, Piacibello, Wanda, Caione, Luisa, Migliardi, Giorgia, Ricciardi, Maria Rosaria, Tafuri, Agostino, Romano, Marco, Salati, Simona, Di Virgilio, Francesco, Ferrari, Sergio, Baccarani, Michele, Ferrari, Davide, Lemoli, Roberto M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 05.01.2012; Americain Society of Hematology
• Subjects: Adenosine Triphosphate - pharmacology; Animals; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Cell Cycle - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Transplantation; Cells, Cultured; Female; Gene Expression Profiling; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Receptors, Purinergic - metabolism; RNA, Messenger - genetics; Signal Transduction; Uridine Triphosphate - pharmacology; Human; Cell proliferation; Acute myelogenous leukemia; Hematology; Acute leukemia; Malignant hemopathy; Severe combined immunodeficient mouse; Cell motility; Signal transduction; Engraftment; Inhibitor; Cell migration; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-370775

Extracellular ATP and UTP nucleotides increase the proliferation and engraftment potential of normal human hematopoietic stem cells via the engagement of purinergic receptors (P2Rs). In the present study, we show that ATP and 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 the cell cycle. Exposure to ATP or UTP inhibited AML-cell migration in vitro. In vivo, xenotransplantation experiments demonstrated that the homing and engraftment capacity of AML blasts and CD34+CD38− cells to immunodeficient mice BM was significantly inhibited by pretreatment with nucleotides. P2R-expression analysis and pharmacologic profiling suggested that the inhibition of proliferation by ATP was mediated by the down-regulation of the P2X7R, which is up-regulated on untreated blasts, whereas the inhibition of chemotaxis was mainly mediated via P2Y2R and P2Y4R subtypes. We conclude that, unlike normal cells, P2R signaling inhibits leukemic cells and therefore its pharmacologic modulation may represent a novel therapeutic strategy.