Authors: Palacios, F.; Abreu, C.; Prieto, D.; Morande, Pablo Elías; Ruiz, S.; Fernández Calero, T.; Naya, H.; Libisch, G.; Robello, C.; Landoni, A. I.; Gabus, R.; Dighiero, G.; Oppezzo, Pablo
Publication Date: 2015.
Language: English.
Abstract:
Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.
Author affiliation: Palacios, F.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
Author affiliation: Abreu, C.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Prieto, D.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Ruiz, S.. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Author affiliation: Fernández Calero, T.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Naya, H.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Libisch, G.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Robello, C.. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Landoni, A. I.. Hospital Maciel Montevideo; Uruguay
Author affiliation: Gabus, R.. Hospital Maciel; Uruguay
Author affiliation: Dighiero, G.. Hospital Maciel; Uruguay
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Galletti, Jeremías Gastón; Cañones, Cristian; Morande, Pablo Elías; Borge, Mercedes; Oppezzo, Pablo; Geffner, Jorge Raúl; Bezares, Raimundo F.; Gamberale, Romina; Giordano, Mirta Nilda
Publication Date: 2008.
Language: English.
Abstract:
The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4+ T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes. Copyright © 2008 by The American Association of Immunologists, Inc.
Author affiliation: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Cañones, Cristian. Academia Nacional de Medicina de Buenos Aires; Argentina
Author affiliation: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Bezares, Raimundo F.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; Argentina
Author affiliation: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Keywords: Inmunología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Palacios, Florencia; Moreno, Pilar; Morande, Pablo Elías; Abreu, Cecilia; Correa, Agustín; Porro, Valentina; Landoni, Ana Ines; Gabus, Raul; Giordano, Mirta Nilda; Dighiero, Guillermo; Pritsch, Otto; Oppezzo, Pablo
Publication Date: 2010.
Language: English.
Abstract:
Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment. © 2010 by The American Society of Hematology.
Author affiliation: Palacios, Florencia. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Moreno, Pilar. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex". Departamento de Inmunología y Medicina Experimental; Argentina
Author affiliation: Abreu, Cecilia. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Correa, Agustín. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Porro, Valentina. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Landoni, Ana Ines. Hospital Maciel; Uruguay
Author affiliation: Gabus, Raul. Hospital Maciel; Uruguay
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex". Departamento de Inmunología y Medicina Experimental; Argentina
Author affiliation: Dighiero, Guillermo. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Pritsch, Otto. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay
Keywords: LEUKEMIA; AID; MICROENVIRONMENT; UNMUTATED; Inmunología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Abreu, Cecilia; Moreno, Pilar; Palacios, Florencia; Borge, Mercedes; Morande, Pablo Elías; Landoni, Ana Inés; Gabus, Raul; Dighiero, Guillermo; Giordano, Mirta Nilda; Gamberale, Romina; Oppezzo, Pablo
Publication Date: 2013.
Language: English.
Abstract:
Among different prognostic factors in chronic lymphocytic leukemia (CLL), we previously demonstrated that lipoprotein lipase (LPL) is associated with an unmutated immunoglobulin profile and clinical poor outcome. Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression are still open questions. Interaction of CLL B-cells with the tissue microenvironment favors disease progression by promoting malignant B-cell growth. Since tissue methylation can be altered by environmental factors, we investigated the methylation status of the LPL gene and the possibility that overexpression could be associated with microenvironment signals. Our results show that a demethylated state of the LPL gene is responsible for its anomalous expression in unmutated CLL cases and that this expression is dependent on microenvironment signals. Overall, this work proposes that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in CLL disease.
Author affiliation: Abreu, Cecilia. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Moreno, Pilar. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Palacios, Florencia. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Landoni, Ana Inés. Hospital Maciel; Uruguay
Author affiliation: Gabus, Raul. Hospital Maciel; Uruguay
Author affiliation: Dighiero, Guillermo. Hospital Maciel; Uruguay
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Oppezzo, Pablo. Universidad de la República; Uruguay
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Almejún, María Belén; Cols, Montserrat; Zelazko, Marta; Oleastro, Matías; Cerutti, Andrea; Oppezzo, Pablo; Cunningham Rundles, Charlotte; Danielian, Silvia
Publication Date: 2013.
Language: English.
Abstract:
Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment ofMyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize withMyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.
Author affiliation: Almejún, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Cols, Montserrat. Mount Sinai School of Medicine. Department of Medicine; Estados Unidos
Author affiliation: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina
Author affiliation: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina
Author affiliation: Cerutti, Andrea. Mount Sinai School of Medicine. Department of Medicine; Estados Unidos
Author affiliation: Oppezzo, Pablo. Instituto Pasteur. Unidad de Proteínas Recombinantes; Uruguay
Author affiliation: Cunningham Rundles, Charlotte. Mount Sinai School of Medicine. Department of Medicine; Estados Unidos
Author affiliation: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Almejún, María Belén; Campos, Bárbara Carolina; Patiño, Virginia; Galicchio, Miguel; Zelazko, Marta; Oleastro, Matías; Oppezzo, Pablo; Danielian, Silvia
Publication Date: 2017.
Language: English.
Abstract:
Background Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. Objective In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. Methods We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. Results Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. Conclusions The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways.
Author affiliation: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Campos, Bárbara Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Patiño, Virginia. Instituto Pasteur; Uruguay
Author affiliation: Galicchio, Miguel. Hospital de Niños Víctor J. Vilela; Argentina
Author affiliation: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Oppezzo, Pablo. Instituto Pasteur; Uruguay
Author affiliation: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Almejún, María Belén; Borge, Mercedes; Colado, Ana; Elías, Esteban Enrique; Podaza, Enrique Arturo; Risnik, Denise Mariel; de Brasi, Carlos Daniel; Stanganelli, Carmen Graciela; Slavutsky, Irma Rosa; Cabrejo, María; Fernández Grecco, Horacio; Bezares, Raimundo Fernando; Cranco, Santiago; Burgos, Rubén Ángel; Sánchez Ávalos, Julio César Américo; Oppezzo, Pablo; Giordano, Mirta Nilda; Gamberale, Romina
Publication Date: 2017.
Language: English.
Abstract:
Sphingosine kinases (SKs) have received the most attention as important enzymes in cancer biology. They participate in the regulation of bioactive sphingolipid metabolism by producing sphingosine-1 phosphate (S1P) which mediates several biological functions, including cell growth, differentiation, cell survival, migration, and angiogenesis among other tasks.1 S1P generation depends on the conversion of sphingosine to S1P, in a reaction catalyzed by two isoforms of SKs, SK1 and SK2, and its levels are tightly controlled via a rapid degradation by intracellular S1P lyases (S1PL) or dephosphorylated by S1P phosphatases.1 Once produced, S1P may function as an intracellular second messenger and/or can be exported outside the cells, where it binds to specific S1P receptors (S1PRs) and initiates downstream signaling pathways, in a paracrine or autocrine manner, in a process known as “inside-out” signaling.
Author affiliation: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Elías, Esteban Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Risnik, Denise Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Stanganelli, Carmen Graciela. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
Author affiliation: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Cabrejo, María. Ciudad Autónoma de Buenos Aires. Sanatorio Municipal "Dr. Julio Méndez"; Argentina
Author affiliation: Fernández Grecco, Horacio. Ciudad Autónoma de Buenos Aires. Sanatorio Municipal "Dr. Julio Méndez"; Argentina
Author affiliation: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; Argentina
Author affiliation: Cranco, Santiago. Instituto Alexander Fleming; Argentina
Author affiliation: Burgos, Rubén Ángel. Instituto Alexander Fleming; Argentina
Author affiliation: Sánchez Ávalos, Julio César Américo. Instituto Alexander Fleming; Argentina
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Morande, Pablo Elías; Borge, Mercedes; Abreu, Cecilia; Galletti, Jeremías Gastón; Zanetti, Samanta Romina; Nannini, Paula Romina; Bezares, Fernando Raimundo; Pantano, Sergio; Dighiero, Guillermo; Oppezzo, Pablo; Gamberale, Romina; Giordano, Mirta Nilda
Publication Date: 2015.
Language: English.
Abstract:
Chronic lymphocytic leukemia (CLL) is the main cause of autoimmune hemolytic anemia (AHA). However, the cellular basis underlying this strong association remains unclear. We previously demonstrated that leukemic B cells from patients with CLL recognize the erythrocyte protein Band 3, a prevalent autoantigen in AHA. Here we show that the major binding site of Band 3 on leukemic cells is an extrinsic protein identified as high-mobility group nucleosome binding protein 2 (HMGN2), a nucleosome-interacting factor which has not been previously reported at the cell surface. T lymphocytes do not express HMGN2 or bind Band 3. Removal of HMGN2 from the cell membrane abrogated the capacity of Band 3-pulsed CLL cells to induce CD4 + T cell proliferation. We conclude that surface HMGN2 in leukemic B cells is involved in Band 3 binding, uptake and presentation to CD4 + T lymphocytes, and as such may favor the initiation of AHA secondary to CLL.
Author affiliation: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Author affiliation: Abreu, Cecilia. Instituto Pasteur de Montevideo. Unidad de Biologia Molecular; Uruguay
Author affiliation: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Author affiliation: Zanetti, Samanta Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Author affiliation: Nannini, Paula Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Author affiliation: Bezares, Fernando Raimundo. Hospital Teodoro Alvarez; Argentina
Author affiliation: Pantano, Sergio. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Dighiero, Guillermo. Hospital Maciel; Uruguay
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo. Unidad de Biologia Molecular; Uruguay
Author affiliation: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Borge, Mercedes; Remes Lenicov, Federico; Nannini, Paula Romina; Alicandú, María M. de los Ríos; Podaza, Enrique Arturo; Ceballos, Ana; Fernandez Grecco, Horacio; Cabrejo, María; Bezares, Raimundo F.; Morande, Pablo Elías; Oppezzo, Pablo; Giordano, Mirta Nilda; Gamberale, Romina
Publication Date: 2014.
Language: English.
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 CLLcells 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.
Author affiliation: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Remes Lenicov, Federico. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina
Author affiliation: Nannini, Paula Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Alicandú, María M. de los Ríos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Ceballos, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina
Author affiliation: Fernandez Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; Argentina
Author affiliation: Cabrejo, María. Sanatorio Municipal Dr. Julio Méndez; Argentina
Author affiliation: Bezares, Raimundo F.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; Argentina
Author affiliation: Morande, Pablo Elías. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay
Author affiliation: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Author affiliation: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas