6533b7d5fe1ef96bd1263ed5

RESEARCH PRODUCT

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

Giovanni D'arenaSimon C. RobsonFabio MalavasiSilvia DeaglioDavide RossiSara SerraAlberto L. HorensteinClaudio TripodoMarta CosciaDavide BrusaGianluca GaidanoTiziana VaisittiLuca LaurentiGiorgio Inghirami

subject

AdenosineCellular differentiationChronic lymphocytic leukemia5'-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; Biochemistry; Immunology; Hematology; Cell BiologyMICROENVIRONMENTCD38BiochemistryACTIVATIONAdenosine TriphosphateCell MovementPhytogenichemic and lymphatic diseasesTumor Cells CulturedChronic5'-NucleotidaseEtoposideLeukemiaCulturedCell DeathTUMOR-GROWTHApyrasePurinergic receptorCell DifferentiationHematologyLymphocyticCDTumor CellsCell biologyAdenosine DiphosphateAutocrine CommunicationLeukemiaReceptorIMMUNE SUPPRESSIONReceptor Adenosine A2ACell SurvivalImmunologyAntineoplastic AgentsAdenosinergicBiologyGPI-Linked ProteinsDAMAGE-INDUCED APOPTOSISAdenosine A2AParacrine signallingAntigens CDParacrine CommunicationmedicineHumansAntigensAutocrine signallingImmunobiologyB-CellCell BiologyDAMAGE-INDUCED APOPTOSIS; T-CELLS; IMMUNE SUPPRESSION; ZAP-70 EXPRESSION; TUMOR-GROWTH; RECEPTOR; CD73; ACTIVATION; CD38; MICROENVIRONMENTmedicine.diseaseAntineoplastic Agents PhytogenicLeukemia Lymphocytic Chronic B-CellSettore MED/15 - MALATTIE DEL SANGUET-CELLSCD73Extracellular SpaceZAP-70 EXPRESSIONCD38

description

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.

https://doi.org/10.1182/blood-2011-08-374728