11 research outputs found

    Chronic lymphocytic leukemia cells increase neutrophils survival and promote their differentiation into CD16 high CD62L dim immunosuppressive subset

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    Reprogramming of neutrophils by malignant cells is well-described for many types of solid tumors, but data remain scarce for hematological diseases. Chronic lymphocytic leukemia (CLL) is characterized for a deep immune dysregulation mediated by leukemic cells that compromises patientÂŽs outcome. Murine models of CLL highlight the relevance of myeloid cells as tumor-driven reprogramming targets. In our study, we evaluated neutrophil reprogramming by CLL cells. We first show that the proportion of the CD16high CD62Ldim neutrophil subset in peripheral blood of CLL patients is increased compared to age-matched healthy donors (HD). In vitro, neutrophils from HD cultured in the presence of CLL cells or conditioned media (CM) from CLL cells exhibited a longer lifespan. Depletion of G-CSF and GM-CSF from CM partially reversed the protective effect. In addition, the proportion of viable neutrophils that displayed a CD16high CD62Ldim phenotype was increased in the presence of CM from CLL cells, being TGF-ÎČ/IL-10 responsible for this effect. Altogether, our results describe a novel mechanism through which CLL cells can manipulate neutrophils.Fil: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: ElĂ­as, Esteban Enrique. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: AlmejĂșn, MarĂ­a BelĂ©n. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernandez Grecco, Horacio. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bezares, Raimundo Fernando. Sanatorio Municipal "Dr. Julio Mendez"; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Borge, Mercedes. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gamberale, Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

    Autologous t-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: Rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies

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    Fil: ElĂ­as, Esteban Enrique. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: AlmejĂșn, MarĂ­a BelĂ©n. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Cordini, Gregorio. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vergara Rubio, Maricef. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de ClĂ­nicas General San MartĂ­n; ArgentinaFil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Cabrejo, MarĂ­a. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: FernĂĄndez Grecco, Horacio. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Bezares, Raimundo Fernando. Universidad de Buenos Aires; ArgentinaFil: Custidiano, MarĂ­a Del Rosario. Sanatorio Municipal Dr. Julio MĂ©ndez; ArgentinaFil: SĂĄnchez Ávalos, Julio CĂ©sar AmĂ©rico. Sanatorio Municipal Dr. Julio MĂ©ndez; ArgentinaFil: Vicente, Ángeles. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Garate, Gonzalo MartĂ­n. Instituto Alexander Fleming; ArgentinaFil: Borge, Mercedes. Instituto Alexander Fleming; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Hospital AlemĂĄn; ArgentinaFil: Gamberale, Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Hospital Aleman; Argentin

    In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia

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    Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 ”M) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gargiulo, Ernesto. Luxembourg Institute Of Health; LuxemburgoFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Fernåndez Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; ArgentinaFil: Cordini, Gregorio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Custidiano, Maria del Rosario. Instituto Alexander Fleming; ArgentinaFil: François, Jean Hugues. Centre Hospitalier de Luxembourg; LuxemburgoFil: Berchem, Guy. Centre Hospitalier de Luxembourg; Luxemburgo. Luxembourg Institute of Health; LuxemburgoFil: Borge, Mercedes. Centre Hospitalier de Luxembourg; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Paggetti, Jerome. Luxembourg Institute of Health; LuxemburgoFil: Moussay, Etienne. Luxembourg Institute of Health; LuxemburgoFil: 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; ArgentinaFil: 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; ArgentinaFil: 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. Luxembourg Institute of Health; Luxemburg

    Sphingosine Kinase 1 Participates In The Activation, Proliferation And Survival Of Chronic Lymphocytic Leukemia Cells

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    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.Fil: AlmejĂșn, MarĂ­a BelĂ©n. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Borge, Mercedes. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: ElĂ­as, Esteban Enrique. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Stanganelli, Carmen Graciela. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones HematolĂłgicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Cabrejo, MarĂ­a. Ciudad AutĂłnoma de Buenos Aires. Sanatorio Municipal "Dr. Julio MĂ©ndez"; ArgentinaFil: FernĂĄndez Grecco, Horacio. Ciudad AutĂłnoma de Buenos Aires. Sanatorio Municipal "Dr. Julio MĂ©ndez"; ArgentinaFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Cranco, Santiago. Instituto Alexander Fleming; ArgentinaFil: Burgos, RubĂ©n Ángel. Instituto Alexander Fleming; ArgentinaFil: SĂĄnchez Ávalos, Julio CĂ©sar AmĂ©rico. Instituto Alexander Fleming; ArgentinaFil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; UruguayFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gamberale, Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

    CXCL12 is a costimulator for CD4+ T cell activation and proliferation in chronic lymphocytic leukemia patients

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    Activated T cells from patients with chronic lymphocytic leukemia (CLL) provide survival and proliferative signals to the leukemic clone within lymphoid tissues. Recruitment of both, CLL cells and T lymphocytes, to this supportive microenvironment greatly depends on CXCL12 production by stromal and myeloid cells. CXCL12 also supplies survival stimuli to leukemic B cells, but whether it exerts stimulatory effects on T lymphocytes from CLL patients is unknown. In order to evaluate the capacity of CXCL12 to increase CD4+ T cell activation and proliferation in CLL patients, peripheral blood mononuclear cells were cultured with or without recombinant human CXCL12 or autologous nurse-like cells, and then T cell activation was induced by anti-CD3 mAb. CXCL12 increases the proliferation and the expression of CD25, CD69, CD154, and IFNγ on CD3-stimulated CD4+ T cells from CLL patients, similarly in T cells from ZAP-70+ to ZAP-70- patients. Autologous nurse-like cells establish a close contact with CD4+ T cells and increase their activation and proliferation partially through a CXCR4-dependent mechanism. In addition, we found that activated T cells in the presence of CXCL12 enhance the activation and proliferation of the leukemic clone. In conclusion, CXCL12 production by lymphoid tissue microenvironment in CLL patients might play a key dual role on T cell physiology, functioning not only as a chemoattractant but also as a costimulatory factor for activated T cells. © 2012 Springer-Verlag.Fil: 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. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: 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. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: 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. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Jancic, Carolina Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Bistmans, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Bezares, Raimundo Fernando. Hospital General de Agudos "Dr. T. Álvarez"; ArgentinaFil: 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. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: 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. Universidad de Buenos Aires. Facultad de Medicina; Argentin

    CXCL12-induced chemotaxis is impaired in T cells from patients with ZAP-70-negative chronic lymphocytic leukemia

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    Background T cells from patients with chronic lymphocytic leukemia may play an important role in contributing to the onset, sustenance, and exacerbation of the disease by providing survival and proliferative signals to the leukemic clone within lymph nodes and bone marrow. Design and Methods By performing chemotaxis assays towards CXCL12, CCL21 and CCL19, we sought to evaluate the migratory potential of T cells from chronic lymphocytic leukemia patients. We next analyzed the chemokine-induced migration of T cells, dividing the chronic lymphocytic leukemia samples according to their expression of the poor prognostic factors CD38 and ZAP70 in leukemic cells determined by flow cytometry. Results We found that T cells from patients with chronic lymphocytic leukemia are less responsive to CXCL12, CCL21 and CCL19 than T cells from healthy adults despite similar CXCR4 and CCR7 expression. Following separation of the patients into two groups according to ZAP-70 expression, we found that T cells from ZAP-70-negative samples showed significantly less migration towards CXCL12 compared to T cells from ZAP-70-positive samples and that this was not due to defective CXCR4 down-regulation, F-actin polymerization or to a lesser expression of ZAP-70, CD3, CD45, CD38 or CXCR7 on these cells. Interestingly, we found that leukemic cells from ZAP-70-negative samples seem to be responsible for the defective CXCR4 migratory response observed in their T cells. Conclusions Impaired migration towards CXCL12 may reduce the access of T cells from ZAP-70-negative patients to lymphoid organs, creating a less favorable microenvironment for leukemic cell survival and proliferation.Fil: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Nannini, Paula Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Sånchez Ávalos, Julio César Américo. Instituto Alexander Fleming; ArgentinaFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

    Surface localization of high-mobility group nucleosome-binding protein 2 (HMGN2) on leukemic B cells from chronic lymphocytic leukemia patients is related to secondary autoimmune hemolytic anemi

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    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.Fil: Morande, Pablo ElĂ­as. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; Argentina. Instituto Pasteur de Montevideo; UruguayFil: Borge, Mercedes. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; ArgentinaFil: Abreu, Cecilia. Instituto Pasteur de Montevideo. Unidad de Biologia Molecular; UruguayFil: Galletti, JeremĂ­as GastĂłn. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; ArgentinaFil: Zanetti, Samanta Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; ArgentinaFil: Nannini, Paula Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; ArgentinaFil: Bezares, Fernando Raimundo. Hospital Teodoro Alvarez; ArgentinaFil: Pantano, Sergio. Instituto Pasteur de Montevideo; UruguayFil: Dighiero, Guillermo. Hospital Maciel; UruguayFil: Oppezzo, Pablo. Instituto Pasteur de Montevideo. Unidad de Biologia Molecular; UruguayFil: Gamberale, Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental; Argentin

    Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia

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    Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1ÎČ in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.Fil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Podaza, Enrique Arturo. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: AlmejĂșn, MarĂ­a BelĂ©n. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: ElĂ­as, Esteban Enrique. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: FernĂĄndez Grecco, Horacio. Sanatorio Municipal Dr. Julio MĂ©ndez; ArgentinaFil: Seija, NoĂ©. Instituto Pasteur de Montevideo; UruguayFil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; UruguayFil: Borge, Mercedes. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gamberale, Romina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

    The effect of ibrutinib on neutrophil and γΎ T cell functions

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    Ibrutinib is a BTK/ITK inhibitor with efficacy for the treatment of various lymphoid cancers, including CLL. Considering that innate and adaptative immune defects are a dominant feature of CLL patients, we evaluated whether in vitro ibrutinib affects the survival and function of neutrophils and cd T cells, key players of the early immune response against microbes. Neutrophils and cd T cells were obtained from peripheral blood of healthy donors and CLL patients. We found that ibrutinib reduces the production of reactive oxygen species (ROS) and bacteria killing capacity, and slightly impairs neutrophil extracellular traps (NETs) production without affecting bacteria-uptake and CD62L-downregulation induced by fMLP or aggregated IgG. In addition, ibrutinib reduces cd T cell activation and CD107a degranulation induced by phosphoantigens or anti-CD3. These findings are in agreement with previous data suggesting that ibrutinib interferes with the protective immune response to pathogens, particularly Mycobacteria and Aspergillus.Fil: Risnik, Denise Mariel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: 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; ArgentinaFil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: 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; ArgentinaFil: Cordini, Gregorio. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Vergara Rubio, Maricef. Universidad de los Andes; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernåndez Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; ArgentinaFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Borge, Mercedes. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Trevani, Analía Silvina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Jancic, Carolina Cristina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gamberale, Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cåtedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin
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