IL-21 controls gene expression in B-chronic lymphocytic leukemia (CLL) cells through micro-RNA regulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42193 | GEO | 2013/09/01
SECONDARY ACCESSION(S): PRJNA179271
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-09-01 | E-GEOD-42193 | biostudies-arrayexpress
Project description:miRNA expression profiles of CLL cells and normal B cells (NBC) treated for 18 hr with 10 ng/ml IL-4, compared with culture with nothing (Ctrl) and the basal (Pre) samples.
2015-06-15 | GSE62137 | GEO
Project description:miRNA expression profiles of CLL cells and normal B cells (NBC) treated for 18 hr with 10 ng/ml IL-4, compared with culture with nothing (Ctrl) and the basal (Pre) samples. 16 CLL patients (8 Pre samples, 15 Ctrl samples, 15 IL-4 samples), 3 NBC (3 Ctrl samples, 3 IL-4 samples)
2015-06-15 | E-GEOD-62137 | biostudies-arrayexpress
Project description:The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.
| S-EPMC4183279 | biostudies-literature
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.
2013-09-01 | GSE42160 | GEO
Project description:Several factors support CLL cell survival in the microenvironment. Under different experimental conditions, IL21 can either induce apoptosis or promote CLL cell survival. To investigate mechanisms involved in the effects of IL21, we studied the ability of IL21 to modulate gene and miRNA expressions in CD40-activated CLL cells. IL21 was a major regulator of chemokine production in CLL cells and it modulated the expression of genes involved in cell movement, metabolism, survival and apoptosis. In particular, IL21 down-regulated the expression of the chemokine genes CCL4, CCL3, CCL3L1, CCL17, and CCL2, while it up-regulated the Th1-related CXCL9 and CXCL10. In addition, IL21 down-regulated the expression of genes encoding signaling molecules, such as CD40, DDR1 and PIK3CD. IL21 modulated a similar set of genes in CLL and normal B-cells (e.g. chemokine genes), whereas other genes, including MYC, TNF, E2F1, EGR2 and GAS-6, were regulated only in CLL cells. An integrated analysis of the miRNome and gene expression indicated that several miRNAs were under IL21 control and these could, in turn, influence the expression of potential target genes. We focused on hsa-miR-663b predicted to down-regulate several relevant genes. Transfection of hsa-miR-663b or its specific antagonist showed that this miRNA regulated CCL17, DDR1, PIK3CD and CD40 gene expression. Our data indicated that IL21 modulates the expression of genes mediating the crosstalk between CLL cells and their microenvironment and miRNAs may take part in this process.
| S-EPMC4549109 | biostudies-literature
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:Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following the commencement of treatment. However, it remains unknown whether higher fitness provides antioncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naïve CLL patients from 144 patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on an in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi, and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p = 0.003), Day 4 (p = 0.001), and Day 5 (p = 0.009). No differences between the groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between the groups. Of these, 14 miRNAs had ≤-1 or ≥1 log2 fold differences. CLL-FIT patients had five exosomal miRNAs with lower expression and nine miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p < 0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/bneg (p = 0.015 and p = 0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK cells (p = 0.047). The absolute number of lymphocytes, including CD19+/CD5+ CLL-cells, was similar between the groups (p = 0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro and with altered circulating and cellular factors indicative of better immune functions and tumor control.
| S-EPMC8151485 | biostudies-literature
Project description:Gene expression profiles of CLL cells and normal B cells (NBC) treated for 18 hr with 10 ng/ml IL-4, compared with culture with nothing (Ctrl) and the basal (Pre) samples. Patient CLL01 was also treated with IL-4 plus 5 mg/ml ERK activation inhibitor peptide I, or IL-4 plus 10 µM NFkB activation inhibitor, and IL-4 plus 100 mg/ml cyclic-pifithrin-α
2014-10-06 | GSE55288 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.
| S-EPMC7530532 | biostudies-literature