Filters
Technology
Platform
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Evi1 is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. Improvement of the therapeutic outcome of leukemia with activated Evi1 is one of the most challenging issues. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here we show that Evi1 directly represses PTEN transcription in the murine bone marrow, which leads to activation of AKT/mTOR signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed remarkable sensitivity to an mTOR inihibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN downregulation, which reveals a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and chromatin immunoprecipitation assays using human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1.
Publication Title
Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Bortezomib (Velcade) is widely used for the treatment of various human cancers, however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that Bortezomib induces proteasome-independent degradation of TRAF6 protein, but not mRNA, in Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized Bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in Bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of Bortezomib due to down-regulation of the proteasomal subunit alpha-1 (PSMA1). To uncover the molecular consequences following loss of TRAF6 in MDS/AML cells, we applied gene expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe novel mechanisms by which TRAF6 is regulated through Bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to Bortezomib by controlling PSMA1 expression.
Publication Title
Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
To identify the target genes of Runx1/Cbfb in MLL fusion leukemia, we performed microarray analysis using control and Runx1/Cbfb-deleted MLL-AF9 cells.
Publication Title
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To identify the target genes of Runx1 in MLL fusion leukemia, we performed microarray analysis using control and Runx1-deficient MLL-ENL leukemia cells.
Publication Title
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Illumina HiSeq 2000
Description
Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2a-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders. Overall design: Differential gene expression profile between epididymal white adipose tissue of Nck2-/- and Nck2+/+ mice by RNA sequencing (Illumina HiSEq 2000)
Publication Title
Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
MicroRNA 155 (miR-155) has been shown to regulate the gene expression of important players of physiological and pathological processes, like hematopoietic lineage differentiation, immunity and inflammation, viral infections, cancer and cardiovascular diseases, among others. Degranulation is an event in which mast cells, upon activation of the FceRI, release their granule content rich in vasoactive amines, proteases and TNFa. Additionally activation of the receptor promotes de novo synthesis of cytokines, chemokines and growth factors. Analysis of bone marrow derived mast cells (BMMC) deficient in miR-155 showed a significant increase in FceRI mediated degranulation and in the release of cytokines like TNFa, IL-6 and IL-13. In addition miR 155-/- mice presented higher anaphylaxis reactions compared to WT mice. Gene expression analysis of BMMC was performed in order to identify intermediaries of FceRI mediated degranulation under the control of miR-155. The results indicate that miR-155 regulates negatively the expression of the regulatory subunits of the kinase PI3Kgamma, Pik3r5 (p101) and Pik3r6 (p84, p87PIKAP), involved in Ca+ influx and degranulation.
Publication Title
miRNA-155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
HM1, HP1a-/-, and HP1b-/- ESC transcriptomes were generated to determine whether depletion of these HP1 proteins influences gene and/or retroelement expression Overall design: mRNA profiles of HP1a and HP1b Knockouts and its corresponding wildtype
Publication Title
Distinct roles of KAP1, HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. Overall design: Hippocampal RNA-Seq profiles of 28 months old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I was compared with placebo adenovector-injected counterparts (4 samples each group)
Publication Title
IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function.
Sample Metadata Fields
No sample metadata fields
View Samples
SRP162274- Homo sapiens
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
Triple-Negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with poor prognosis due to its propensity to form metastases. Unfortunately, the current treatment options are limited to chemotherapy such that identification of actionable targets are needed. The receptor tyrosine kinase AXL plays a role in the tumor cell dissemination and its expression in TNBC correlates with poor patients? survival. Here, we explored whether exploiting an AXL knockdown gene signature in TNBC cells may offer an opportunity for drug repurposing. To this end, we queried the PharmacoGx pharmacogenomics platform with an AXL gene signature which revealed Phenothiazines, a class of Dopamine Receptors antagonists (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if drugs may be active to limit growth and metastatic progression of TNBC cells, similarly to AXL depletion. We found that the Phenothiazines were able to reduce cel l invasion, proliferation and viability, and also increased apoptosis of TNBC cells in vitro. Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, these drugs showed were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics are novel anti-tumor and anti-metastatic agents that could potentially be repurposed, in combination with standard chemotherapy, for use in TNBC. Overall design: RNA-seq of the Triple Negative Breast Cancer cell line MDA-MB-231 treated with siCt or siAXL Differential gene expression profile between MDA-MB-231 siCt and siAXL by RNA sequencing (Illumina HiSEq 2000)
Publication Title
AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To determine the modulation of gene expression of mouse BMDCs in the presence of living intracellular Leishmania amazonensis amastigotes
Publication Title
Sorting of Leishmania-bearing dendritic cells reveals subtle parasite-induced modulation of host-cell gene expression.
Sample Metadata Fields
Sex, Age
View Samples