title: CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death.
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.
authors: Human Genetics Foundation (HuGeF), Turin, Italy.
authors: Sara
authors: S
authors: Serra
authors: Alberto L
authors: AL
authors: Horenstein
authors: Tiziana
authors: T
authors: Vaisitti
authors: Davide
authors: D
authors: Brusa
authors: Davide
authors: D
authors: Rossi
authors: Luca
authors: L
authors: Laurenti
authors: Giovanni
authors: G
authors: D'Arena
authors: Marta
authors: M
authors: Coscia
authors: Claudio
authors: C
authors: Tripodo
authors: Giorgio
authors: G
authors: Inghirami
authors: Simon C
authors: SC
authors: Robson
authors: Gianluca
authors: G
authors: Gaidano
authors: Fabio
authors: F
authors: Malavasi
authors: Silvia
authors: S
authors: Deaglio
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001081:Apyrase / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D058851:GPI-Linked Proteins; D043705:Receptor, Adenosine A2A; D000244:Adenosine Diphosphate; D005047:Etoposide; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine