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GSE32523
Homo sapiens
8 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human T-cell Acute lymphoblastic Leukemia cell line CEM was transfected with either shRNA against ZMIZ1 or scrambled shRNA. Four (non-paired) biological replicates of each condition had mRNA assays performed using Affymetrix HG_U133_plus_2 arrays, with 54675 probe-sets. A supplementary Excel workbook holding the same processed data as the series matrix file is provided, with some probe set annotation, and a simple statistical comparison. The raw (.CEL) files are also provided.
Publication Title
Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
Illumina HiSeq 2000
Description
Hepatocellular carcinoma (HCC) accounts for the majority of malignant liver tumors and results in many deaths each year, emphasizing the need for new therapies. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Therefore, we performed RNA sequencing experiment to determine the transcriptome change in the HepG2 cells upon treatment of MI-503, a small molecule inhibitor of the menin-MLL1 interaction with optimized drug-like properties Overall design: HepG2 cells were plated in the 12-well plates at the initial concentration of 0.4x106 cells/ml and treated with 3 µM MI-503 or DMSO (0.25%) in triplicates. After 3 days of treatment viable cell number was adjusted to the original concentration in the DMSO treated samples and the same dilution factor was used to adjust cell number in the MI-503 treated cells. Media was changed and compound or DMSO was re-supplied at that time. Cells were harvested after 3 more days of incubation.
Publication Title
Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of <i>PEG10</i> and Blocks Hepatocellular Carcinoma.
Sample Metadata Fields
Treatment, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
The Polymerase Associated Factor (PAFc) complex is an epigenetic regulating complex that has been shown to to be important for Acute Myeloid Leukemias harboring an MLL chromosomal translocations, such as MLL-AF9 leukemias. This study describes the transcriptomic profiling of AML cells following genetic deletion of the PAFc subunit Cdc73. Overall design: Cdc73floxed cells were transformed to an AML using MLL-AF9 oncogene transduction. The cells were also transduced with a 4OHT inducible CreER. The cells were then treated for 24 or 48 hours with 4OHT to induce genetic excision of Cdc73 and polyA mRNA was isolated for sequencing of the transcriptome. Biological duplicates are labelled _1 and _2.
Publication Title
The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia.
Sample Metadata Fields
Cell line, Treatment, Subject, Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
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. ChIP-Seq showed that Zmiz1 selectively co-bound only a subset of Notch-regulated enhancers. This led to hypothesize that Zmiz1 regulates only a subset of Notch1 target genes. To investigate this, we performed RNA-Seq on four 8946 cell linesin which L1601P (activated Notch1) or Zmiz1 were expressed alone or in combination. Zmiz1 induced ~10% of Notch target genes. The Notch target gene that was most strongly induced by Zmiz1 was Myc. Our data suggest that Zmiz1 selectively amplifies a subset of Notch target genes with strong amplification of Myc. Overall design: RNA-Seq in a murine T-ALL cell line
Publication Title
The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Chromosomal translocations affecting Mixed Lineage Leukemia (MLL) gene result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of novel, highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mice models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate for the first time that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.
Publication Title
Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HiSeq 2000
Description
BCL6 inhibitor induces derepression of BCL6 target genes and shows a similar transcriptional program to BCL6 siRNA Overall design: Genome-wide profiling of mRNA transcript levels in human DLBCL cell line with BCL6 inhibitor and DMSO control.
Publication Title
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands. Overall design: gene expression profiles of DLBCL cases
Publication Title
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 40 Downloadable Samples
- IlluminaHiSeq2500
Description
We compare the performance of two library preparation protocols (poly(A) and exome capture) in in vitro degraded RNA samples Overall design: VcaP cell were grown, and treated with MDV3100 (enzalutamide) or DHT (dihydrotestosterone), intact RNA was isolated and samples were prepared in technical triplicates using two library preparation protocol. Also cells were subject to in vitro degradation through incubation of the whole cell lysate in 37C for increasing amounts of time. Following incbation paired capture and poly(A) libraries were prepared.
Publication Title
The use of exome capture RNA-seq for highly degraded RNA with application to clinical cancer sequencing.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
As duodenum is an important Vitamin D target organ, transcriptomic analyses were performed in this tissue.
Publication Title
A vitamin D receptor selectively activated by gemini analogs reveals ligand dependent and independent effects.
Sample Metadata Fields
Age, Specimen part
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
The quality of maternal care in early-life plays a crucial role in mammalian neurodevelopment. Augmented maternal care (AMC) is a well-established rodent model of enhanced neonatal care. Rats that have undergone AMC have improved stress resilience and cognition compared with rats that have experienced normal levels of maternal care or adverse neonatal stress. However, the epigenomic basis of long-lived responses to AMC has not been previously explored. Thus, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to assess DNA cytosine methylation, gene expression, and miRNA expression, respectively. The integrated results identify a suite of 20 prioritized candidates impacted by AMC. Overall, these results identified AMC-induced regulatory differences in genes related to neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation in addition to the expected stress response genes. Together, these unbiased results represent a key progression in understanding the complex mechanisms underlying the early-life mechanisms for AMC programming stress resiliency. Overall design: DNA methylation and RNA were assayed in augmented maternal care male rats as well as controls.
Publication Title
Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples