MLN4924 in chronic lymphocytic leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE44864 | GEO | 2013/03/05
SECONDARY ACCESSION(S): PRJNA192430
REPOSITORIES: GEO
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Project description:CLL cells obtained from patients with CLL were treated with MLN4924 to determine whether NFkB transcription targets were affected by the drug. CLL cells were treated with 1 microM MLN4924 or vehicle control for 24 hours. Cells were collected by centrifugation and B-cell were purified using negative selection (B cell purification Kit, Multenyi Biotech). RNA was isolated and submitted for Gene expression analysis
2013-03-05 | E-GEOD-44864 | biostudies-arrayexpress
Project description:Inflammatory factors that activate NFkB play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL) but are not addressed specifically by current therapies. Interleukin-1 (IL-1) is a master-regulator of inflammation that is inhibited safely in humans by the IL-1 receptor antagonist anakinra. Anakinra (K) was found to inhibit NFkB activity in CLL cells in an IL-1 receptor independent manner and had properties of an intracellular anti-oxidant in vitro.
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Project description:The two B-cell non-Hodgkin lymphoma (NHL) entities chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) show recurrent chromosomal gains of 3q25 q29, 12q13 q14 and 18q21-q22. The pathomechanisms affected by these aberrations are not understood. The aim of this study was to identify genes, located within these gained regions, which control cell death and cell survival of MCL and CLL cancer cells. Blood samples from 24 CLL and 6 MCL patients as well as 6 cell lines representing both malignancies were analyzed by gene expression profiling. By comparison of genomic DNA and gene expression, 72 candidate genes were identified. We performed a limited RNAi screen with these candidates in order to identify genes affecting cell survival. CCDC50, SERPINI2 and SMARCC2 mediated a reduction of cell viability in primary CLL cells as well as in cell lines. Gene knock down and a NFkB reporter gene assay revealed that CCDC50 is required for survival in MCL and CLL cells and controls NFkB signaling. This SuperSeries is composed of the SubSeries listed below.
2010-06-03 | GSE16413 | GEO
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 23 CLL patients (10 Pre samples, 23 Ctrl samples, 23 IL-4 samples, 1 IL-4 plus ERK inhibitor sample, 1 IL-4 plus NFkB inhibitor sample, 1 IL-4 plus Pifithrin sample), 13 NBC (10 Pre samples, 10 Ctrl samples, 13 IL-4 samples)
2014-10-06 | E-GEOD-55288 | biostudies-arrayexpress
Project description:Purpose:To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Methods: We employed piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL.
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Project description:Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have recently been proposed as potential new therapies for hematological malignancies. Chronic Lymphocytic Leukemia (CLL) remains incurable despite the introduction of new treatments. CLL cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as bone marrow and lymph nodes. Here, we investigated gene expression modifications in CLL cells following treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. Experiment Overall Design: CLL cells obtained from 14 patients were treated in vitro with a concentration of 1mM VPA for 4 hours. VPA effects on gene expression were thereafter studied using Affymetrix technology
2009-09-17 | E-GEOD-14973 | biostudies-arrayexpress
Project description:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.
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Project description:In this study, we used RNA-sequencing to characterize the gene-expression profiles of CLL cells sensitive and resistant to dasatinib and define a specific gene-expression signature associated with drug sensitivity. Specifically, cells were isolated from the blood of 16 newly diagnosed, unselected CLL patients prior to any treatment and classified as responders or non-responders based on in vitro drug cytotoxicity assays. RNA-sequencing analysis of both treated and untreated samples revealed 154 genes differentially expressed between responders and non-responders and, among these, 31 genes were predictive of response in untreated samples. Cells sensitive to dasatinib exhibit increased expression of genes associated with stress signaling, metabolic pathways, including glycolysis, and immune response, including proinflammatory components. Neither of the responder and non-responder groups was enriched for any of the genetic aberrations commonly associated with CLL, as determined by gene mutation and copy-number analysis. We employed the Library of Integrated Network-Based Cellular Signatures (LINCS) database for validation of the obtained gene expression profiles and show, in sum, that dasatinib may represent a viable therapeutic option in a group of CLL patients preselected by gene-expression profiling.
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Project description:Purpose:To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Methods: We employed piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. To address if the fludarabine-resistant HG3 cells were transcriptionally different at a global level compared to their parental cells, we performed RNA-sequencing of three pairs of HG3 pools
2016-03-31 | E-GEOD-75844 | biostudies-arrayexpress
Project description:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions. Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia
2013-09-20 | E-GEOD-50252 | biostudies-arrayexpress