Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA212072 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase. To gain further insights into mechanisms of cytotoxicity of this combination, we applied unbiased mass spectrometry proteomics to CCRF-CEM cells, a human T-cell acute lymphoblastic leukemia cell line, treated with vehicle, asparaginase alone, the GSK3 inhibitor BRD0705 (which phenocopies Wnt/STOP pathway activation), or the combination of asparaginase and BRD0705.
2019-03-29 | PXD013061 | Pride
Project description:The development of a clinically relevant xenograft model of pediatric acute lymphoblastic leukemia, using a 4-drug treatment regimen designed to mimic pediatric remission induction therapy. Relapse and acquired drug resistance in T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. This study was designed to establish a preclinical model of resistance to induction therapy in childhood T-ALL to examine the emergence of drug resistance and identify novel therapies. We performed transcription profiling by array of human CD45-positive human lymphocytes from patients with acute pediatric lymphoblastic leukemia, and from xenografted NOD/SCID mice treated with vincristine, daunorubicin, dexamethasone and L-asparagine. Several different treatment regimes were used in this study (VLXD, VLXDR, VLXD2, VXL and VLXD2-ALL31) and are summarised in the protocols associated with this submission.
2013-11-01 | E-MEXP-3916 | biostudies-arrayexpress
Project description:Cellular drug resistance is associated with an unfavorable prognosis in pediatric acute lymphoblastic leukemia (ALL). To identify genes conferring resistance to antileukemic agents, we analyzed the expression of >12,700 genes in sensitive and resistant ALL cells obtained at diagnosis from 174 patients. This revealed 42, 59, 54 and 22 genes (Pâ¤0.001) that were differentially expressed in B-lineage ALL that was sensitive versus resistant to prednisolone, vincristine, asparaginase or daunorubicin, respectively, with prediction accuracies of 71-76%. Notably, 149 of the discriminating genes have not been previously associated with resistance to these anticancer agents. These included carbohydrate-metabolism and transcription-associated genes for prednisolone, cytoskeleton and extracellular matrix genes for vincristine, ribosomal protein and translation-associated genes for asparaginase, and RAS signaling and nucleosome remodeling complex genes for daunorubicin. The identification of novel genomic determinants of cellular drug resistance provides new insights for overcoming drug resistance in acute lymphoblastic leukemia.
2008-06-15 | E-GEOD-635 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. Gene expression was measured in the CUTLL1 T-ALL cell line after treatment with GSI or DMSO (solvent control). Cells were collected 12h and 48h after treatment. This was performed for 3 replicates.
2014-10-27 | E-GEOD-61869 | biostudies-arrayexpress
Project description:In this work, we generated hundreds of millions of Hi-C paired end sequence reads for three different human cells (RL follicular lymphoma cell line, primary tumor B-cells from an acute lymphoblastic leukemia patient, and MHH-CALL-4 B-cell acute lymphoblastic leukemia cell line) using the Hi-C technique. An in-house Bioinformatics software pipeline was developed and applied to map sequence reads to the human reference genome, producing a large data set of high-quality and high-resolution chromosome contacts. Our computational analysis on these data reveal some interesting properties of human genome conformation, including conformational conservation and variation of the genomes of different cells, intra- and inter-chromosomal interactions, aberrant chromosomal translocation, spatial gene clusters, spatial gene-gene interactions, and spatial gene-regulatory-element interaction. Furthermore, we derived spatial interactions between functional elements (genes, transcription factor binding sites) from the chromosomal interaction data. The data were then used to generate chromosome-/genome-wide gene-gene interaction networks, transcription factor binding site (TFBS) â TFBS networks, and gene-TFBS networks. Remarkably, the connectivity in both networks shows the hallmark features of scale-free networks, suggesting that spatial interactions of gene-gene, gene-TFBS, and TFBS-TFBS in a genome are far from random. Three different human cells (RL follicular lymphoma cell line, primary tumor B-cells from an acute lymphoblastic leukemia patient, and MHH-CALL-4 B-cell acute lymphoblastic leukemia cell line) were analyzed
2015-11-01 | E-GEOD-73924 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. CD34+ cells of 2 healthy donors are cultured on a OP9-GFP or OP9-DLL1 feeder layer.
2014-10-27 | E-GEOD-62000 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. CD34+ cells of 4 healthy donors are cultured on a OP9-GFP or OP9-DLL1 feeder layer.
2014-10-27 | E-GEOD-61871 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. Gene expression was measured in sorted T-cell subsets of 4 healthy donors.
2014-10-27 | E-GEOD-61873 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. Gene expression profiling of 64 T-ALL patient samples
2014-10-27 | E-GEOD-61866 | biostudies-arrayexpress
Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. Gene expression was measured 15 patients diagnosed with T-ALL. 8 patients were NOTCH1 wild type, 7 patients were NOTCH1 mutant.
2014-10-27 | E-GEOD-61863 | biostudies-arrayexpress