GATA3 induces human T cell commitment following Notch-induced T-lineage specification (expression)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Inge Van de Walle
PROVIDER: E-GEOD-76348 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:The stepwise conversion of multipotent precursors into committed T-cell progenitors depends on several transcriptional regulators, but the interplay between these factors is still obscure. This is particularly true in human since the core early Notch signalling pathway also supports NK cell development and requires tight regulation for efficient T-lineage commitment and differentiation. Here, we show that GATA3, in contrast to TCF1, induces T-lineage commitment following NOTCH1-induced T-lineage specification through direct regulation of at least 3 distinct processes: repression of NK-cell fate, activation of T-lineage genes to promote further differentiation, and downmodulation of Notch signalling activity. GATA3-mediated repression of the NOTCH1 target gene DTX1 hereby is essential to induce T-lineage commitment at the expense of NK cell differentiation. Thus, human T-lineage commitment is dependent on the precise collaboration of several transcriptional regulators that integrate through both positive and negative regulatory loops. Gene expression was profiled in CT CD34+ cells after transduction with control or GATA3 and coculture on OP9-DL1 for 48h. Cells were collected 48h after coculture and sorted for CD45+EGFP+. 3 independent experiments were performed on 3 different thymus donors.
2016-04-06 | E-GEOD-71752 | 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: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 4 different T-ALL cell lines (HPB-ALL, DND-41, TALL-1 and ALL-SIL) after treatment with GSI or DMSO (solvent control). Cells were collected 12h and 48h after treatment.
2014-10-27 | E-GEOD-61870 | 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
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:T-cell acute lymphoblastic leukemia (T-ALL) is genetically heterogeneous and can be classified into genetic subclasses based on protein coding gene expression profiles. Thus far, long noncoding RNAs (lncRNAs), representing one of the largest fractions of the human transcriptome, remained unexplored as genetics markers for distinct T-ALL subtypes. Therefore, we here determined, for the first time, lncRNA expression profiles in lymphoblasts of 64 T-ALL patients and identified a robust set of lncRNAs that discriminate previously established genetic subtypes of human T-ALL. Half of these lncRNAs were positively correlated with the expression levels of neighboring protein coding genes located in their immediate vicinity, hinting towards cis-regulatory functions. In addition, gene set enrichment analysis showed that these lncRNA signatures were also recapitulated in human T-ALL cell lines representative for the different genetic subclasses, suggesting that these tumor lines could serve as valuable in vitro cellular model systems for further functional lncRNA studies. Finally, comparison of T-ALL lncRNA signatures with those from stage-specific normal developing human thymocytes revealed multiple ectopically expressed, putative oncogenic lncRNAs. Our data identify lncRNAs novel genetic markers in T-ALL biology and warrant further in depth investigations towards landscaping of their specific role in thymopoiesis and leukemogenesis. Gene expression profiles of 10 different T-ALL cell lines
2016-05-17 | E-GEOD-74272 | biostudies-arrayexpress
Project description:The stem cell gene LIN28B was recently shown to be overexpressed in a foetal-like subgroup of juvenile myelomonocytic leukaemia. Given the involvement of LIN28B in a variety of solid paediatric cancers, we conducted a meta-analysis of LIN28B levels using publicly available gene expression data of 1361 paediatric leukaemia samples. Interestingly, this analysis revealed LIN28B overexpression in 102 childhood leukaemia patients (7.5%), suggesting oncogenic activity for LIN28B in the context of paediatric haematological diseases. As the mode of action of LIN28B during normal and malignant haematopoiesis remains largely unexplored, we subsequently analysed the transcriptional consequences of LIN28B modulation on normal and malignant haematopoietic cells and identified the long non-coding RNA (lncRNA) H19 as the first LIN28B-regulated lncRNA. K562 cells were retrovirally transduced with shRNA GN36578 against LIN28B and a shRNA-miR non-targeting control TRH1103 (both Transomic), selected with puromycin and hybridized on Agilent microarray.
2016-04-07 | E-GEOD-79980 | biostudies-arrayexpress
Project description:The stem cell gene LIN28B was recently shown to be overexpressed in a foetal-like subgroup of juvenile myelomonocytic leukaemia. Given the involvement of LIN28B in a variety of solid paediatric cancers, we conducted a meta-analysis of LIN28B levels using publicly available gene expression data of 1361 paediatric leukaemia samples. Interestingly, this analysis revealed LIN28B overexpression in 102 childhood leukaemia patients (7.5%), suggesting oncogenic activity for LIN28B in the context of paediatric haematological diseases. As the mode of action of LIN28B during normal and malignant haematopoiesis remains largely unexplored, we subsequently analysed the transcriptional consequences of LIN28B modulation on normal and malignant haematopoietic cells and identified the long non-coding RNA (lncRNA) H19 as the first LIN28B-regulated lncRNA. Oci-AML3 cells were retrovirally transduced with MSCV-PIG-LIN28B and MSCV-PIG-empty vectors (gifts from Johua Mendel lab), selected with puromycin and hybridized on Agilent microarray.
2016-04-07 | E-GEOD-79979 | 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