CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death

Luca Laurenti, S Serra, Al Horenstein, T Vaisitti, D Brusa, D Rossi, G D'Arena, M Coscia, C Tripodo, G Inghirami, Sc Robson, G Gaidano, F Malavasi, S. Deaglio

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Extracellular adenosine (ADO), generated from ATP or ADP through the concerted action of the ectoenzymes CD39 and CD73, elicits autocrine and paracrine effects mediated by type 1 purinergic receptors. We have tested whether the expression of CD39 and CD73 by chronic lymphocytic leukemia (CLL) cells activates an adenosinergic axis affecting growth and survival. By immunohistochemistry, CD39 is widely expressed in CLL lymph nodes, whereas CD73 is restricted to proliferation centers. CD73 expression is highest on Ki-67(+) CLL cells, adjacent to T lymphocytes, and is further localized to perivascular areas. CD39(+)/CD73(+) CLL cells generate ADO from ADP in a time- and concentration-dependent manner. In peripheral blood, CD73 expression occurs in 97/299 (32%) CLL patients and pairs with CD38 and ZAP-70 expression. CD73-generated extracellular ADO activates type 1 purinergic A2A receptors that are constitutively expressed by CLL cells and that are further elevated in proliferating neoplastic cells. Activation of the ADO receptors increases cytoplasmic cAMP levels, inhibiting chemotaxis and limiting spontaneous drug-induced apoptosis of CLL cells. These data are consistent with the existence of an autocrine adenosinergic loop, and support engraftment of leukemic cells in growth-favorable niches, while simultaneously protecting from the action of chemotherapeutic agents.
Original languageEnglish
Pages (from-to)6141-6152
Number of pages12
JournalBlood
Volume118
DOIs
Publication statusPublished - 2011

Keywords

  • 5'-Nucleotidase
  • Adenosine
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Antigens, CD
  • Antineoplastic Agents, Phytogenic
  • Apyrase
  • Autocrine Communication
  • Cell Death
  • Cell Differentiation
  • Cell Movement
  • Cell Survival
  • Etoposide
  • Extracellular Space
  • GPI-Linked Proteins
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Paracrine Communication
  • Receptor, Adenosine A2A
  • Tumor Cells, Cultured

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