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Homo sapiens
19 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Identification of genes that are differentially regulated in fibroblasts derived from dysplastic oral mucosa and oral squamous cell carcinoma compared to fibroblasts derived from normal oral mucosa.
Publication Title
Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples
GSE34949- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Deregulated accumulation of myofibroblasts (MF) is central to liver fibrosis pathogenesis, but the mechanisms controlling myofibroblast fate remain poorly understood. Here we investigated whether Hedgehog (Hh) signaling regulates MF fate by modulating MF metabolism.
Publication Title
Hedgehog controls hepatic stellate cell fate by regulating metabolism.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus, Homo sapiens
- 66 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The TLX1 and TLX3 transcription factor oncogenes play an important role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL)1,2. Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This Systems Biology analysis defined TLX1 and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, network structure analysis of this hierarchical network identified RUNX1 as an important mediator of TLX1 and TLX3 induced T-ALL, and predicted a tumor suppressor role for RUNX1 in T-cell transformation. Consistent with these results, we identified recurrent somatic loss of function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 atop of an oncogenic transcriptional network controlling leukemia development, demonstrate power of network analysis to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor suppressor gene in T-ALL.
Publication Title
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 59 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Transgenic expression of key transcritpion factors inducing T-cell leukemias in mice.
Publication Title
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The experiment was designed in order to knock down the expression of TLX3 gene in T-ALL cell line
Publication Title
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The experiment was designed in order to knock down the expression of TLX1 gene in T-ALL cell line
Publication Title
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
Somatic ribosomal protein defects have recently been described in cancer, yet their impact on cellular transcription and translation remain poorly understood. Here we integrated mRNA sequencing, ribosome footprinting, polysomal RNA seq and quantitative mass spectrometry datasets obtained from an isogenic mouse lymphoid cell model in order to study the T-cell acute lymphoblastic leukemia (T-ALL) associated R98S mutation in ribosomal protein L10 (RPL10 R98S). RPL10 R98S induced changes in protein levels were to a much larger extent caused by transcriptional then translational changes and RPL10 R98S cells showed a gene signature corresponding to deregulation of hematopoietic transcription factors. Phosphoserine phosphatase (PSPH), a key enzyme in serine biosynthesis, displayed elevated transcription and translation and was one of the proteins showing the strongest upregulation in RPL10 R98S cells. Increased Psph protein levels were confirmed in RPL10 R98S engineered JURKAT cells and in hematopoietic cell cultures derived from Rpl10 R98S knock-in mice. Moreover, elevated serine and glycine biosynthesis in RPL10 R98S cells was supported by metabolic flux analyses. Analysis of PSPH expression levels in T-ALL patient samples revealed that PSPH upregulation is a generalized phenomenon in this disease, associated with elevated circulating serine and glycine levels. Addition of serine and glycine enhanced survival of stromal and myeloid cells, suggesting supportive effects on the hematopoietic niche. Finally, reduction of PSPH expression levels in T-ALL cell lines suppressed their in vitro proliferation and their capacity to expand in T-ALL xenograft models. In conclusion, transcriptome, translatome and proteome analysis of the RPL10 R98S mutation identified RPL10 R98S driven induction of cellular serine biosynthesis. Whereas serine metabolism has been implicated in cancer via PHGDH amplification, this is the first report supporting dependence of ALL cells on the serine biosynthesis enzyme PSPH. Overall design: 3 biological replicates for each condition (RPL10 R98S, RPL10 WT)
Publication Title
Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 28 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC.
Publication Title
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.
Sample Metadata Fields
No sample metadata fields
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