title: Purinergic signaling inhibits human acute myeloblastic leukemia cell proliferation, migration, and engraftment in immunodeficient mice.
abstract: 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.
authors: Department of Hematology and Oncological Sciences, L. & A. Seràgnoli, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy. salvestrinivalentina@libero.it
authors: Valentina
authors: V
authors: Salvestrini
authors: Roberta
authors: R
authors: Zini
authors: Lara
authors: L
authors: Rossi
authors: Sara
authors: S
authors: Gulinelli
authors: Rossella
authors: R
authors: Manfredini
authors: Elisa
authors: E
authors: Bianchi
authors: Wanda
authors: W
authors: Piacibello
authors: Luisa
authors: L
authors: Caione
authors: Giorgia
authors: G
authors: Migliardi
authors: Maria Rosaria
authors: MR
authors: Ricciardi
authors: Agostino
authors: A
authors: Tafuri
authors: Marco
authors: M
authors: Romano
authors: Simona
authors: S
authors: Salati
authors: Francesco
authors: F
authors: Di Virgilio
authors: Sergio
authors: S
authors: Ferrari
authors: Michele
authors: M
authors: Baccarani
authors: Davide
authors: D
authors: Ferrari
authors: Roberto M
authors: RM
authors: Lemoli
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D017690:Cell Transplantation; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011983:Receptors, Purinergic / Q000378:metabolism*; D015398:Signal Transduction; D014544:Uridine Triphosphate / Q000494:pharmacology*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011983:Receptors, Purinergic; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate