title: Involvement of the P2X7-NLRP3 axis in leukemic cell proliferation and death.
abstract: Lymphocyte growth and differentiation are modulated by extracellular nucleotides and P2 receptors. We previously showed that the P2X7 receptor (P2X7R or P2RX7) is overexpressed in circulating lymphocytes from chronic lymphocytic leukemia (CLL) patients. In the present study we investigated the P2X7R/NLRP3 inflammasome axis in lymphocytes from a cohort of 23 CLL patients. P2X7R, ASC and NLRP3 were investigated by Western blot, PCR and transfection techniques. P2X7R was overexpressed and correlated with chromosome 12 trisomy in CLL patients. ASC mRNA and protein were also overexpressed. On the contrary, NLRP3 was dramatically down-modulated in CLL lymphocytes relative to lymphocytes from healthy donors. To further investigate the correlation between P2X7R, NLRP3 and cell growth, NLRP3 was silenced in THP-1 cells, a leukemic cell line that natively expresses both NLRP3 and P2X7R. NLRP3 silencing enhanced P2X7R expression and promoted growth. On the contrary, NLRP3 overexpression caused accelerated apoptosis. The P2X7R was also up-modulated in hematopoietic cells from NLRP3-KO mice. In conclusion, we show that NLRP3 down-modulation stimulates P2X7R expression and promotes growth, while NLRP3 overexpression inhibits cell proliferation and stimulates apoptosis. These findings suggest that NLRP3 is a negative regulator of growth and point to a role of the P2X7R/NLRP3 axis in CLL.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Salaro
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Falzoni
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Francesca Saveria
authors.initials: FS
authors.lastname: Amoroso
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Franceschini
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Alba Clara
authors.initials: AC
authors.lastname: Sarti
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bonora
authors.affiliation: Department of Medical Sciences, Section of Hematology, University of Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavazzini
authors.affiliation: Department of Medical Sciences, Section of Hematology, University of Ferrara, Italy.
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.affiliation: Department of Medical Sciences, Section of Hematology, University of Ferrara, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Ciccone
authors.affiliation: Department of Medical Sciences, Immunogenetics Unit, Human Genetics Foundation, Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Audrito
authors.affiliation: Department of Medical Sciences, Immunogenetics Unit, Human Genetics Foundation, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.affiliation: Murcia Biomedical Research Institute (IMIB), Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrin
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Medical Sciences, Section of Hematology, University of Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D000074084:THP-1 Cells
chemical_list: D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C546468:P2RX7 protein, human; C402202:PYCARD protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7