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SRP058619
Homo sapiens
8 Downloadable Samples
IlluminaHiSeq2000
Description
Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of ß-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of ß-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of ß-Catenin in these T-ALL cells and demonstrate that the MYC 3'' enhancer required ß-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1. Overall design: Four T-ALL cell lines (RPMI8402, HPB-ALL, Jurkat, CCRF-CEM) were treated with DMSO (control) or PKF115-584 (310nM) for 3hrs. Gene expression changes were measured with Cufflinks comparing the 4 control with the 4 treated samples.
Publication Title
β-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
We have generated a mouse model for tumor initiation carrying a mutation in APC and lacking IKKa in intestinal epithelial cells. IKKa-deficient intestinal cells primarily failed to generate adenomas, and the few adenomas arising in this background displayed a significant reduction in cell proliferation. Using an in vitro model for intestinal tumoroids (derived from adenoma initiating cells), we have performed RNA sequencing of wild type and IKKa-deficient intestinal tumoroids. This has demonstrated that epithelial IKKa controls transcription of stem cell-related genes and genes associated with proliferation and apoptosis. Overall design: RNA sequencing of IKKa WT and KO tumoroids, done in triplicates
Publication Title
IKKα is required in the intestinal epithelial cells for tumour stemness.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Hematopoietic Stem Cells (HSC) are originated during embryonic development from endothelial-like cells located in the ventral side of the dorsal aorta around day E10-12 of murine development. This region is called AGM for Aorta/Gonad/Mesonephros and refers to the tissues around the hemogenic aorta. Cells that emerge from the endothelium and show hematopoietic traits can be distinguished by the expression of the c-kit receptor and finally acquire the CD45 marker.
Publication Title
Hematopoietic stem cell development requires transient Wnt/β-catenin activity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Robles-Valero et al. report a tumor suppression role for the otherwise oncogenic Vav1 Rho GEF. This paradoxical action is mediated by the catalysis-independent buffering of Notch1 signaling in immature T cells.
Publication Title
A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Gene expression profile between Parp-2-/- and wild-type hematopoietic stem/progenitor cells at basal and to the early response (2.5 hours) to 5 Gy total body irradiation
Publication Title
Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Gene expression from MCF7 breast cancer cells at different times of TNFa incubation:pcs2 and 14-3-3 transduced cells
Publication Title
Inhibition of specific NF-κB activity contributes to the tumor suppressor function of 14-3-3σ in breast cancer.
Sample Metadata Fields
Time
View Samples- Mus musculus
- 4 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional factors such as ETS and E2F4 and co-repressors like p130, HDACs and mSin3A, p27 binds to promoters of multiple genes leading to their repression. The p27-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27 and over-expression of p27-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p271 as a transcriptional regulator of genes relevant for oncogenesis.
Publication Title
p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 22 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
To determine genes in FL HSCs that are sensitive to Notch signagling, E14.5 FL cells were cultured on DL1( to stimulate Notch signaling). Cells were cultured in the presence of DMSO (vehicle control) or gamma secretase inhibitor (1uM) for 4 hrs or 10hrs. Gamma secretase inhibitor was used to inhibit Notch signaling. SLAM-LSKs were sorted and used for RNA preparation.
Publication Title
The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
NF-kB has been linked to doxorubicin-based chemotherapy resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined, however its functional consequences in terms the spectrum of NF-kB -dependent genes expressed and, thus, the impact on tumour cell behaviour are unclear.
Publication Title
Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The NF-B pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-B response is regulated by the activation state of the IB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-B is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-B activation and the potential importance of NF-B in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-B activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo.
Publication Title
The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples