Expression profile of isolated lymphoblasts from mice treated with vehicle or SAHM1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE18351 | GEO | 2009/11/12
SECONDARY ACCESSION(S): PRJNA118099
REPOSITORIES: GEO
Similar Datasets
Project description:NOTCH proteins regulate signaling pathways involved in cellular differentiation, proliferation and death. Overactive Notch signaling as been observed in numerous cancers and has been extensively studied in the context of T-cell acute lymphoblastic leukemia (T-ALL) where more than 50% of pateints harbour mutant NOTCH1. Small molecule modulators of these proteins would be important for understanding the role of NOTCH proteins in malignant and normal biological processes. We were interested to measure the global gene expression changes in leukemic cells isolated from mice harbouring a NOTCH1-driven genetically engineered T-cell leukemia after treatment with SAHM1, a synthetically stabilized α-helical peptide derived from the MAML1 co-activator protein. Experiment Overall Design: A genetically engineered murine model of NOTCH1-driven T-ALL was developed by retroviral transduction of murine bone marrow with a mutant NOTCH1 allele commonly observed in human T-ALL patients. Transplantation of transduced cells gave rise to T-ALL that was quantifiable by bio-luminescence in our model. After established leukemia was evident by continually increased tumor burden (luminescence) mice were either treated with vehicle alone (5% DMSO in Hank's buffered saline solution) or SAHM1 (30 mg/kg, twice daily, intraperitoneal injection). After five days of treatment, mice receiving SAHM1 had a significant decrease in tumor growth. To measure a pharmacodynamic effect on Notch signaling, circulating lymphoblasts were collected from vehicle- (n=3) and SAHM1-treated (n=3) mice and gene expression profiles were generated.
2009-11-28 | E-GEOD-18351 | biostudies-arrayexpress
Project description:NOTCH proteins regulate signaling pathways involved in cellular differentiation, proliferation and death. Overactive Notch signaling as been observed in numerous cancers and has been extensively studied in the context of T-cell acute lymphoblastic leukemia (T-ALL) where more than 50% of pateints harbour mutant NOTCH1. Small molecule modulators of these proteins would be important for understanding the role of NOTCH proteins in malignant and normal biological processes. We were interested to measure the global changes in gene expression upon treatment of the human T-ALL cell lines HPB-ALL and KOPT-K1 with either vehicle alone (DMSO) or SAHM1, an alpha-helical hydrocarbon stapled peptide derived from the MAML1 co-activator protein.
2009-11-12 | GSE18198 | GEO
Project description:NOTCH proteins regulate signaling pathways involved in cellular differentiation, proliferation and death. Overactive Notch signaling as been observed in numerous cancers and has been extensively studied in the context of T-cell acute lymphoblastic leukemia (T-ALL) where more than 50% of pateints harbour mutant NOTCH1. Small molecule modulators of these proteins would be important for understanding the role of NOTCH proteins in malignant and normal biological processes. We were interested to measure the global changes in gene expression upon treatment of the human T-ALL cell lines HPB-ALL and KOPT-K1 with either vehicle alone (DMSO) or SAHM1, an alpha-helical hydrocarbon stapled peptide derived from the MAML1 co-activator protein. Experiment Overall Design: Triplicate cultures of KOPT-K1 or HPB-ALL cells were treated with either DMSO alone or SAHM1 (20 uM) for 24 hours. Total RNA was extracted and hybridized to Affymetrix human U133 plus 2.0 microarrays (three arrays per treatment per cell line for a total of 12 arrays).
2009-11-28 | E-GEOD-18198 | biostudies-arrayexpress
Project description:Notch is normally activated by cleavage and nuclear translocation of its intracellular domain (ICN1), which turns on downstream target genes. Human T cell acute lymphoblastic leukemia (T-ALL), an aggressive immature T cell malignancy, is associated with Notch 1 gain-of-function mutations in more than 50% of the cases. Efforts to date to identify direct Notch1 targets have been confounded by the lack of a method to turn Notch1 on in a controlled fashion in T-ALL cells that are poised to respond to Notch signals. Of note, because Notch signaling activates transcriptional repressors that feedback to dampen the expression of many target genes (a process referred to as incoherent logic), it is likely that many direct targets are missed in Notch off analyses, which are further complicated by an inability to identify direct targets in a clear-cut fashion. We have overcome this limitation by developing a GSI washout method that results in the rapid translocation of activated Notch1 to the nucleus. We intend to use this method to study the assembly and loading of transcriptional complexes onto downstream targets, the kinetics of target activation. To date, our efforts have been devoted to comparing the gene expression signature of Notch-on and Notch-off in the human T-ALL cell line CUTLL. In addition to previously identified Notch1 target genes, we have also identified a series of novel genes upregulated by GSI washout in the presence of cycloheximide, suggesting that they are likely to be direct targets. Additional controls included transduction of cells with dominant negative MAML1, a specific antagonist of canonical Notch1 signaling, prior to Notch1 reactivation, and a mock GSI washout to control for cycloheximide effects. CUTLL1 cells are cultured in triplicates with different treatments. Total RNA was prepared and hybridized to Affymetrix human U133 plus 2.0 microarrays
2011-07-06 | E-GEOD-29544 | biostudies-arrayexpress
Project description:Notch is normally activated by cleavage and nuclear translocation of its intracellular domain (ICN1), which turns on downstream target genes. Human T cell acute lymphoblastic leukemia (T-ALL), an aggressive immature T cell malignancy, is associated with Notch 1 gain-of-function mutations in more than 50% of the cases. Efforts to date to identify direct Notch1 targets have been confounded by the lack of a method to turn Notch1 on in a controlled fashion in T-ALL cells that are poised to respond to Notch signals. Of note, because Notch signaling activates transcriptional repressors that feedback to dampen the expression of many target genes (a process referred to as incoherent logic), it is likely that many direct targets are missed in Notch off analyses, which are further complicated by an inability to identify direct targets in a clear-cut fashion. We have overcome this limitation by developing a GSI washout method that results in the rapid translocation of activated Notch1 to the nucleus. We intend to use this method to study the assembly and loading of transcriptional complexes onto downstream targets, the kinetics of target activation. To date, our efforts have been devoted to comparing the gene expression signature of Notch-on and Notch-off in the human T-ALL cell line CUTLL. In addition to previously identified Notch1 target genes, we have also identified a series of novel genes upregulated by GSI washout in the presence of cycloheximide, suggesting that they are likely to be direct targets. Additional controls included transduction of cells with dominant negative MAML1, a specific antagonist of canonical Notch1 signaling, prior to Notch1 reactivation, and a mock GSI washout to control for cycloheximide effects.
2011-07-06 | GSE29544 | GEO
Project description:Mastermind-like 1 (MAML1) functions as a co-activator in the NOTCH signaling pathway. A truncated version of its wild type form, the so-called dominant-negative MAML1 (DN-MAML1) , lacks the transactivation domains that are needed for stimulation of gene expression. The aim of the study was to characterize the effects of NOTCH signaling pathway inhibition in human trophoblast stem cells (TSCs) by overexpression of DN-MAML1.
2023-06-30 | GSE233140 | GEO
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
Project description:To determine role of Notch signaling in AML leukemia initiating cells we used a conditional mouse knock-in model of Notch1-IC to induce Notch1-IC expression in MLL-AF9 transformed LGMP. WT and Notch1-IC+ LGMP were analyzed to determined genes controlled by Notch signaling.
2013-01-18 | GSE42260 | GEO
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