title: The expression of sphingosine-1 phosphate receptor-1 in chronic lymphocytic leukemia cells is impaired by tumor microenvironmental signals and enhanced by piceatannol and R406.
abstract: Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L(+), BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow-resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38(low) counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues.
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1121, Argentina;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Borge
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida, Facultad de Medicina, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires 1121, Argentina;
authors.forename: Federico
authors.initials: F
authors.lastname: Remes Lenicov
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina;
authors.forename: Paula R
authors.initials: PR
authors.lastname: Nannini
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina;
authors.forename: María M
authors.initials: MM
authors.lastname: de los Ríos Alicandú
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1121, Argentina;
authors.forename: Enrique
authors.initials: E
authors.lastname: Podaza
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida, Facultad de Medicina, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires 1121, Argentina;
authors.forename: Ana
authors.initials: A
authors.lastname: Ceballos
authors.affiliation: Sanatorio Municipal Dr. Julio Méndez, Ciudad Autónoma de Buenos Aires 1405, Argentina;
authors.forename: Horacio
authors.initials: H
authors.lastname: Fernández Grecco
authors.affiliation: Sanatorio Municipal Dr. Julio Méndez, Ciudad Autónoma de Buenos Aires 1405, Argentina;
authors.forename: María
authors.initials: M
authors.lastname: Cabrejo
authors.affiliation: Hospital T. Álvarez, Ciudad Autónoma de Buenos Aires 1406, Argentina; and.
authors.forename: Raimundo F
authors.initials: RF
authors.lastname: Bezares
authors.affiliation: Unidad de Proteínas Recombinantes, Instituto Pasteur Montevideo, Montevideo 11400, Uruguay.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Morande
authors.affiliation: Unidad de Proteínas Recombinantes, Instituto Pasteur Montevideo, Montevideo 11400, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Oppezzo
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1121, Argentina;
authors.forename: Mirta
authors.initials: M
authors.lastname: Giordano
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires 1425, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1121, Argentina; rominagamberale@fibertel.com.ar.
authors.forename: Romina
authors.initials: R
authors.lastname: Gamberale
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001402:B-Lymphocytes; D023201:CD40 Ligand / Q000096:biosynthesis; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008246:Lysophospholipids / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008875:Middle Aged; D010078:Oxazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051562:Proto-Oncogene Proteins c-bcr / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology*; D019718:Receptors, CXCR4; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000276:immunology; D000081025:Sphingosine-1-Phosphate Receptors; D013267:Stilbenes / Q000494:pharmacology*; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D019718:Receptors, CXCR4; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D013267:Stilbenes; D023201:CD40 Ligand; C060506:sphingosine 1-phosphate; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D013110:Sphingosine