Genome-Wide Expression Profiling of B-CLL cells vs Healthy B cells cultured in high density
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100801 | GEO | 2017/07/06
SECONDARY ACCESSION(S): PRJNA393111
REPOSITORIES: GEO
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Project description:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ vs. CD38-CD49d- CLL cells, we demonstrated overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also upregulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38-CD49d- cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express VCAM-1, the CD49d ligand, likely through TNFα over-production. These effects were apparent in BMB from CD38+CD49d+CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1-transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as a part of a consecutive chain of events ultimately leading to improved survival of CLL cells.
2009-03-03 | GSE14560 | GEO
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) 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.
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Project description:We used microarrays to analyze gene expression following treatment of leukemic B cells with the Hsp90 inhibitor 17-DMAG. Gene expression profiling reveals the role of SOCS3 in cytokine signaling in CLL Primary cells from CLL patients were isolated and treated in vitro with 17-DMAG. Cells were collected for viability, gene expression analysis and cell signaling and migration assays.
2016-07-01 | E-GEOD-76546 | biostudies-arrayexpress
Project description:Increased survival of primary B-CLL cells cultured in high cell density: Evidence for activation of pathways also induced by stromal cells. Expression profiles of B-CLL cells before and after three different survival-inducing culture conditions: (1) stromal cell coculture [HCo], (2) stromal cell conditioned medium [CM], (3) high cell density cultures [CD]. Controls without survival-inducing culture conditions are included [0]. Peripheral blood samples were obtained from B-CLL patients.
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Project description:Increased survival of primary B-CLL cells cultured in high cell density: Evidence for activation of pathways also induced by stromal cells.
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Project description:We examined copy number changes in the genomes of B cells from 58 patients with chronic lymphocytic leukemia (CLL) using representational oligonucleotide microarray analysis (ROMA), a form of comparative genomic hybridization (CGH), at a resolution exceeding previously published studies. We observed at least one genomic lesion in each CLL sample and considerable variation in the number of abnormalities from case to case. Virtually all abnormalities previously reported were also observed here, most of whichwere indeed highly recurrent. We observed the boundaries of known events with greaterclarity and identified previously undescribed lesions, some of which were recurrent. Weprofiled the genomes of CLL cells separated by the surface marker CD38, and foundevidence of distinct subclones of CLL within the same patient. We discuss the potential applications of high resolution CGH analysis in a clinical setting. Keywords: Genetic modification, polymorphonuclear cell (PMN)
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Project description:In the present study, the methylation profiling (MeDIP) was carried out in 14 treatment-naive, early stage (Rai stage 0-2) CLL patients and pooled 19+ normal controls. To find an association of methylation with IGHV mutation status, CLL patients were further segregated into IGHV unmutated (n=9) and IGHV mutated (n=5) subgroups. The methylation signature obtained for CLL versus nornal controls and; unmutated versus mutated CLL was integrated with gene expression profile of these patients and the results were correlated with clinical outcome.
2017-05-29 | GSE81936 | GEO
Project description:Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that while targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of IL-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift towards TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.
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Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-βII and the subsequent activation of NF-κB in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-β knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-βII- NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine Nemo/ IKK-gamma dependent gene expression changes in bone marrow stromal cells (BMSCs) induced by co-culturing with leukemic B-cells (CLL)
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