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Oncogenesis of T-ALL and non-malignant consequences of overexpressing NOTCH1

ABSTRACT: We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found.

ORGANISM(S): Mus musculus

PROVIDER: GSE12948 | GEO | 2008/10/27

SECONDARY ACCESSION(S): PRJNA110977

REPOSITORIES: GEO

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Transcription profiling of mouse after ICN1 overexpression from retroviral vectors were introduced into bone marrow cell - soncogenesis of T-ALL and non-malignant consequences of overexpressing NOTCH1

Project description:We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. Experiment Overall Design: Expression analysis, array-based comparative genomic hybridization and spectral karyotyping.

2008-11-13 | E-GEOD-12948 | biostudies-arrayexpress

Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1.

Project description:Mutations resulting in overexpression of intracellular Notch1 (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic CD4(+)8(+) T cell receptor (TCR)-alphabeta(+) cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by posttranslational modification. The first tumorigenic cells are detected among more immature CD4(-)8(+)TCR-alphabeta(-) cells that give rise to monoclonal tumors with a single, unique TCR-beta chain and diverse TCR-alpha chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-alpha rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyotype (SKY) analysis, none of the tumors arise because of genomic instability.

| S-EPMC2585834 | biostudies-literature

Genome-wide analysis of intracellular notch1(ICN1) targets in gamma delta T cells (gd T cells).

Project description:We performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) for ICN1 in thymic gd T cells from neonates of C57BL/6 mice. Sequence reads for ICN1 and Input were aligned with the mouse reference genome (mm10) by bowtie program (v1.0.0), and peak detection and identification of ICN1 binding sites were obtained with MACS program (v1.4.2). ChIP-seq data revealed that 12%, 6% and 47% of ICN1 binding sites were within -10kb upstream of transcription start site, +10kb downstream of 3'end and the bodies of genes, respectively. The other of ICN1 binding sites was intergenic. We also found that ICN1 directly bound -5.4kb upstream of transcript start site of IL-7 receptor alpha (IL-7Ra) locus, which were estimated as a new promoter region of IL-7Ra. Some of ICN1 binding sites (e.g. TCF1 promoter) were consistent with previous reports, but others (e.g. Nr4a1 promoter) were novel. These suggests that ICN1 was associated with a lot of transcriptional regulation in gd T cells.

2014-11-14 | GSE56756 | GEO

Mapping of Notch1 binding sites in a mouse immature T cell line

2014-04-02 | GSE46114 | GEO

Genome-wide analysis of intracellular notch1(ICN1) targets in gamma delta T cells (gd T cells).

2014-11-14 | E-GEOD-56756 | biostudies-arrayexpress

The PIAS-like coactivator Zmiz1 directly and selectively coregulates Notch1 in T-cell development and leukemia [ChIP-Seq]

Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. In order to determine whether this interaction occured at chromatin, we performed ChIP-Seq. We identified significant overlap between ICN1, Rbpj, and Zmiz1 peaks. 75% of overlapping ICN1/Rbpj peaks overlapped with Zmiz1 (HA) peaks (273 peaks). The size of Zmiz1 (HA) peaks had moderate correlation with the size of Rbpj and ICN1 peaks. Like Rbpj and ICN1 peaks, Zmiz1 (HA) peaks were associated with activating H3K27ac, H3K4me1, and H3K4me3 chromatin marks and were devoid of repressive H3K27me3 marks. These data suggest that Zmiz1 is a selective Notch regulator. It co-binds only a subset of ICN1 and Rbpj-regulated sites.

2015-10-28 | GSE66146 | GEO

Mapping of Notch1 binding sites in a mouse immature T cell line

Project description:We used an immature mouse T cell line engineered to express a biotinylated form of the cleaved form of Notch1 (ICN1). ICN1-bound sites were precipitated with streptavidin-coated beads and subjected to ChIP-sequencing. Beko cells correspond to a spontaneous T lymphoma immature cell line derived from a TCRb deficient mouse. These cells were engineered to express a biotin-tagged-ICN1 and the bacterial biotin ligase BirA (Bio-ICN1) or just BirA as a control (Bio). Chromatin from both cell lines was subjected to strepatavidin-mediated precipitation and subjected to sequencing with the Illumina GAII sequencer as single end 36 base pair reads.

2014-04-02 | E-GEOD-46114 | biostudies-arrayexpress

The PIAS-like coactivator Zmiz1 directly and selectively coregulates Notch1 in T-cell development and leukemia [ChIP-Seq]

2015-10-28 | E-GEOD-66146 | biostudies-arrayexpress

Gene expression analysis of murine day 6 embryoid bodies (EBs ) with or without Notch1 (ICN1) induction.

Project description:Analysis of CD41 single positive, VE-cadherin single positive, double positive, and double negatvie populations among 7AAD-CD45- cells from day 6 EBs Doxycline-inducible ICN1 ES cells were differentiated into EBs and ICN1 was induced from day 3-5. Non-induced or induced day 6 EBs were dissociated and subjected to FACS sorting and RNA extraction.

2010-11-14 | E-GEOD-19951 | biostudies-arrayexpress

Comparison of the transcriptome of TEL-JAK2- versus activated NOTCH1 (ICN1)-induced T cell acute lymphoblastic leukemias (mouse)

Project description:The TEL-JAK2 fusion oncogene and the ICN1 activated allele of NOTCH1 are the result of specific chromosomal translocations in T cell acute lymphoblastic leukemia (T-ALL). Mouse models of these diseases (TEL-JAK2 transgenic mice; Carron C. et al. Blood (2000); a bone marrow transplantation model for ICN1-induced T-ALL) were used to compare the transcriptional program specific to each oncoprotein in mouse models of these leukemias. Tumor load was >50% leukemic cells in all selected organs.

2013-09-28 | GSE51243 | GEO

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