IL-21 regulates miRNA expression in B-chronic lymphocytic leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42160 | GEO | 2013/09/01
SECONDARY ACCESSION(S): PRJNA179273
REPOSITORIES: GEO
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Project description:B-cell chronic lymphocytic leukemia (CLL) is a common type of leukemia, characterized by the progressive accumulation of CD5+ “mature” monoclonal B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. Although circulating CLL cells are non-dividing cells, prone to spontaneous apoptosis, their progressive accumulation is the result of a dynamic balance between cell death and proliferation and a high turn-over rate has been related to a poor prognosis. Indeed, CLL cells are protected from apoptosis and proliferate in specific niches within the lymphoid tissues and the bone marrow. CLL cells show variable expression of IL-21R that can be up-regulated by cell activation via CD40. CD40-activated CLL cells phosphorylate STAT-1 and STAT-3 and undergo apoptosis in response to IL-21 stimulation. By gene-expression profiling we found out that IL-21 modulates the expression of several genes including cytokine and chemokine genes and genes involved in cell survival and apoptosis in CD40-activated CLL cells.
2013-09-01 | GSE42158 | GEO
Project description:B-cell chronic lymphocytic leukemia (CLL) is a common type of leukemia, characterized by the progressive accumulation of CD5+ “mature” monoclonal B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. Although circulating CLL cells are non-dividing cells, prone to spontaneous apoptosis, their progressive accumulation is the result of a dynamic balance between cell death and proliferation and a high turn-over rate has been related to a poor prognosis. Indeed, CLL cells are protected from apoptosis and proliferate in specific niches within the lymphoid tissues and the bone marrow. CLL cells show variable expression of IL-21R that can be up-regulated by cell activation via CD40. CD40-activated CLL cells phosphorylate STAT-1 and STAT-3 and undergo apoptosis in response to IL-21 stimulation. By gene-expression profiling we found out that IL-21 modulates the expression of several genes including cytokine and chemokine genes and genes involved in cell survival and apoptosis in CD40-activated CLL cells. PBMCs were isolated from heparinized blood obtained from 13 untreated patients diagnosed with CLL on the basis of clinical and immunophenotypic criteria. PBMCs were isolated by Ficoll density gradient centrifugation and characterized by immunofluorescence and FACS analysis. When residual non B-cells exceeded 10%, B cells were enriched by negative selection with antibody-coated magnetic beads (CD2-beads, Dynal, Oslo, Norway) to obtain a >95% pure CD19+/CD5+ B cell population. B-CLL cells were pre-activated on adherent CD40L-transduced L cells for 48-36h and then stimulated with IL-21 or medium only for additional 18h. Total RNA was isolated from samples using TriZol (Invitrogen) reagent.
2013-09-01 | E-GEOD-42158 | biostudies-arrayexpress
Project description:B-cell chronic lymphocytic leukemia (CLL) is a common type of leukemia, characterized by the progressive accumulation of CD5+ “mature” monoclonal B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. Although circulating CLL cells are non-dividing cells, prone to spontaneous apoptosis, their progressive accumulation is the result of a dynamic balance between cell death and proliferation and a high turn-over rate has been related to a poor prognosis. Indeed, CLL cells are protected from apoptosis and proliferate in specific niches within the lymphoid tissues and the bone marrow. By gene-expression profiling we found out that IL-21 modulates the expression of several genes including cytokine and chemokine genes and genes involved in cell survival and apoptosis in CD40-activated CLL cells. To gain information of the possible mechanisms involved in the regulation of these genes we tested the possibility that IL-21 may act through specific miRNA regulation. PBMCs were isolated from heparinized blood obtained from 13 untreated patients diagnosed with CLL on the basis of clinical and immunophenotypic criteria. PBMCs were isolated by Ficoll density gradient centrifugation and characterized by immunofluorescence and FACS analysis. When residual non B-cells exceeded 10%, B cells were enriched by negative selection with antibody-coated magnetic beads (CD2-beads, Dynal, Oslo, Norway) to obtain a >95% pure CD19+/CD5+ B cell population. B-CLL cells were pre-activated on adherent CD40L-transduced L cells for 48-36h and then stimulated with IL-21 or medium only for additional 18h. Total RNA was isolated from samples using TriZol (Invitrogen) reagent. This Series represents 9 of the 13 cases.
2013-09-01 | E-GEOD-42160 | biostudies-arrayexpress
Project description:<p>Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+CD19+ B cells in peripheral lymphoid organs, bone marrow and blood. In this study we analyze matched whole genome sequencing and RNA-seq data from CLL patients to characterize the mutational processes operative throughout tumor evolution.</p> <p>Source of tumor and normal DNA used is patient PBMC or B cells and saliva respectively.</p>
| phs000879 | dbGaP
Project description:Chronic Lymphocytic Leukemia (CLL) cells multiply in secondary lymphoid tissue but the mechanisms leading to their proliferation are still uncertain. In addition to BCR-triggered signals, other microenvironmental factors might well be involved. In proliferation centres, leukemic B cells are in close contact with CD4+CD40L+ T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. We then defined an IL-21-induced gene signature in CLL, containing components of JAK-STAT and apoptosis pathways, and this signature could be detected in lymph node (LN) samples from patients. Finally, we could detect IL-21 RNA and protein in LN, and IL-21 production ex vivo by LN CD4+CXCR5+ follicular helper T cells. These results indicate that, in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40 and IL-21. Targeting these signaling pathways might offer new venues for treatment of CLL. CLL cells were cultured under different conditions for 16 hours and then sorted to purity as CD20+ CD5+ cells.
2013-10-07 | E-GEOD-50572 | biostudies-arrayexpress
Project description:Chronic Lymphocytic Leukemia (CLL) cells multiply in secondary lymphoid tissue but the mechanisms leading to their proliferation are still uncertain. In addition to BCR-triggered signals, other microenvironmental factors might well be involved. In proliferation centres, leukemic B cells are in close contact with CD4+CD40L+ T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. We then defined an IL-21-induced gene signature in CLL, containing components of JAK-STAT and apoptosis pathways, and this signature could be detected in lymph node (LN) samples from patients. Finally, we could detect IL-21 RNA and protein in LN, and IL-21 production ex vivo by LN CD4+CXCR5+ follicular helper T cells. These results indicate that, in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40 and IL-21. Targeting these signaling pathways might offer new venues for treatment of CLL.
2013-10-07 | GSE50572 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant CD5+ B lymphocytes (CLL cells) in the peripheral blood, and their progressive infiltration in lymphoid organs. Despite the efforts made, CLL remains an incurable disease. It is therefore crucial to continue searching for new therapeutic agents and targets. Arsenic trioxide (ATO) induces apoptosis in all CLL cases and it could constitute an efficient therapy for this disease. We used Affimetrix microarray technology to characterize the global gene expression profile underlying CLL cell response to ATO, with the aim of identifying the ATO mechanism of action as well as new therapeutic targets in CLL.
2016-03-21 | GSE78207 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant CD5+ B lymphocytes (CLL cells) in the peripheral blood, and their progressive infiltration in lymphoid organs. MMP-9 plays an important role in cell migration and survival, contributes to CLL pathogenesis by proteolytic and non-proteolytic mechanisms and may constitutive a therapeutic target. We used Affimetrix microarray technology to characterize the global gene expression profile of chronic lymphocytic leukemia (CLL) cells upon MMP-9 transfection. The aim was to establish whether MMP-9 regulates gene expression and to identify new therapeutic targets in CLL.
2016-03-21 | GSE78174 | GEO
Project description:Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL. To identify gene expression related to microenvironmental stimuli in B-cell Chronic Lymphocytic Leukemia (CLL) cells in vivo, expression profiles of CLL cells purified (>95%) from bone marrow (BM) and peripheral blood (PB) were compared. Paired BM and PB samples from 6 individuals were used for this analysis.
2011-07-25 | E-GEOD-30896 | biostudies-arrayexpress
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and BM. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor (MIF) and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both immune-mediated neutralization or blockade of CD84 induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 milatuzumab shows a decrease in CD84 mRNA levels milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 message. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. 3 samples; incubated with PBS, MIF, or IL-8.
2013-03-01 | E-GEOD-37430 | biostudies-arrayexpress