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GSE49089
Mus musculus
15 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 32 Downloadable Samples
Illumina HiSeq 2000
Description
Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Overall design: Primary leukemia cells harvested from spleens were sorted into immunophenotypic subpopulations (Mac-1High, Mac-1LowKit–Sca-1–, Mac-1LowKit+Sca-1–, and Mac-1LowKit+Sca-1+). RNA was extracted from this subpopulations of cells and submitted for RNA sequencing.
Publication Title
NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies.
Publication Title
NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 117 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), characterized by aneuploidy and poor outcome, is unknown. Here, using complementary genome-wide profiling approaches, we show that hypodiploid ALL comprises two major subtypes that differ in the severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24-31 chromosomes frequently harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL cases with 32-39 chromosomes are characterized by TP53 alterations (88%), almost half of which are present in non-tumor cells, and have alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras and PI3K signaling pathways, and are sensitive to PI3K inhibition, indicating that these drugs should be explored as a new therapeutic strategy for this frequently lethal form of leukemia.
Publication Title
The genomic landscape of hypodiploid acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 41 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Gene expression profiling was performed of Pax5 wild type bone marrow subsets from common lymphoid progenitors through to Hardy stage F cells. These cells were obtained by flow sorting of bone marrow.
Publication Title
The genomic landscape of hypodiploid acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HiSeq 2000
Description
Purpose: The goal of the study was to integrate verified signals from previous genetic association studies with gene expression and pathway analysis for discovery of new candidate genes and signalling networks, relevant for rheumatoid arthritis (RA). Method:RNA-seq based expression analysis of 377 genes from previously verified RA-associated loci was performed in blood cells from 5 newly diagnosed, non-treated RA patients, 7 patients with treated RA and 12 healthy controls. Differentially expressed genes sharing a similar expression pattern in treated and untreated RA sub-groups were selected for pathway analysis. A set of “connector” genes derived from pathway analysis was then tested for differential expression in the initial discovery cohort. Results: 11 qualifying genes were selected for pathway analysis and grouped into 2 evidence-based functional networks, containing 29 and 27 additional “connector” molecules. The expression of genes, corresponding to connector molecules was then tested in the initial RNA-seq data. 3 genes showed similar expression difference in both treated and non-treated RA patients and additional nine genes were differentially expressed in at least one patients' group compared to healthy controls. Conclusion: Integration of RNA-seq data with findings from association studies, and consequent pathway analysis implicate new candidate genes in the pathogenesis of RA. Overall design: Illumina RNA-seq was performed on RNA from pereferial blood mononuclear cells taken from 12 healthy individuals, 5 untreated RA patients, and 7 treated RA patients
Publication Title
Discovery of new candidate genes for rheumatoid arthritis through integration of genetic association data with expression pathway analysis.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina HiSeq 2500
Description
RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptome of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2 under these conditions whereas retained RNA-binding capacity of TTP-AA to 3’UTRs caused profound changes in the transcriptome and translatome, altered NF-?B-activation and induced cell death. Increased TTP binding to the 3''UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-?B-signaling pathway. Taken together, our study uncovers a role for TTP in NF-?B-signaling and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control feedback signaling during the inflammatory response. Overall design: Comparison of the transcriptomes of TTP knockout macrophages inducibly expressing GFP, GFP-TTP or GFP-TTP-AA (S52A, S178A) phosphorylation mutant during 1h LPS stimulation. 3 biological replicates per genotype and condition.
Publication Title
The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HiSeq 2500
Description
The presence of the PTPN22 risk variant (1858T) is associated to several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk variant on T cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve CD4+ T cells carrying two PTPN22 risk alleles overexpress a limited number of genes including CFLAR and 4-1BB important for cytotoxic T cell differentiation. Moreover, an increased number of cytotoxic EOMES+ CD4+ T cells were observed in PTPN22 risk allele carriers, which negatively correlated with a decreased number of naïve T cells in older individuals. No difference in the frequency of other CD4+ T cell subsets (Th1, Th17, Tfh, Treg) was observed in PTPN22 risk allele carriers and Treg suppressive capacity was not altered. Finally, in synovial fluids of RA patients, an accumulation of EOMES+ CD4+ T cells was observed with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, our data provide a novel mechanism of action of PTPN22 risk variant on CD4+ T-cell differentiation and identify EOMES+ CD4+ T cell as a relevant T cell subset in RA. Overall design: Healthy blood donors were selected based PTPN22 genotype, and RNA-sequencing was done on CD4 T cells
Publication Title
EOMES-positive CD4<sup>+</sup> T cells are increased in PTPN22 (1858T) risk allele carriers.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We performed gene expression profiling on in vitro derived PGCs, undifferentiated ESCs, and somatic cells from the EB to examine germ cell expression in ESC-derived cells
Publication Title
Single cell analysis facilitates staging of Blimp1-dependent primordial germ cells derived from mouse embryonic stem cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Background
Publication Title
Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.
Sample Metadata Fields
No sample metadata fields
View Samples