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

Valentina Salvestrini, Roberta Zini, Lara Rossi, Sara Gulinelli, Rossella Manfredini, Elisa Bianchi, Wanda Piacibello, Luisa Caione, Giorgia Migliardi, Maria Rosaria Ricciardi, Agostino Tafuri, Marco Romano, Simona Salati, Francesco Di Virgilio, Sergio Ferrari, Michele Baccarani, Davide Ferrari, Roberto M. Lemoli

Research output: Contribution to journalArticle

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 G 0 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 upregulated 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.

Original languageEnglish
Pages (from-to)217-226
Number of pages10
JournalBlood
Volume119
Issue number1
DOIs
Publication statusPublished - Jan 5 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Salvestrini, V., Zini, R., Rossi, L., Gulinelli, S., Manfredini, R., Bianchi, E., Piacibello, W., Caione, L., Migliardi, G., Ricciardi, M. R., Tafuri, A., Romano, M., Salati, S., Di Virgilio, F., Ferrari, S., Baccarani, M., Ferrari, D., & Lemoli, R. M. (2012). Purinergic signaling inhibits human acute myeloblastic leukemia cell proliferation, migration, and engraftment in immunodeficient mice. Blood, 119(1), 217-226. https://doi.org/10.1182/blood-2011-07-370775