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GSE75086
Homo sapiens
11 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
While disease recurrence remains the outstanding clinical challenge in acute myeloid leukemia (AML), the basis of relapse remains poorly characterized and thereby preventing effective therapeutic targeting. We performed gene expression analysis of human AML patient samples in addition to in vitro and in vivo assays of leukemic cell survival and self-renewal using xenograft modeling. These molecular and functional analyses afforded the identification of unique target genes that support recurrence. Preclinical modeling using these novel targets provided proof-of-principle for combination therapies towards more effective and durable suppression of AML regrowth.
Publication Title
Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Increasing evidence suggests that cancer arises from cells that are capable of initiating and sustaining neoplastic tissue growth, termed cancer stem cells (CSCs). Of central scientific and clinical relevance, cells with CSC properties are enriched for chemo- and radiation resistance and therefore may represent a population of cells that must be therapeutically targeted to prevent cancer recurrence/relapse 1. Human CSCs were first isolated in neoplastic hematopoietic tissue that manifests leukemias such as adult acute myeloid leukemia (AML) 2. AML stem cells represent a benchmark model of human CSC biology, ultimately motivating foundational studies leading to the identification of CSCs from solid tumours such as breast and colon 3. Independent of tissue type, a consistent feature of CSCs is their uncontrolled self-renewal capacity and differentiation blockade that have been commonly related to aberrant activation of pro-oncogenic events such as dysregulation of CBP/p300 transcriptional regulation involving -catenin 4. However, the transcriptional networks involving CBP/p300/-catenin complex have been shown to be equally critical to maintain normal stem cell (SCs) self-renewal for tissue homeostasis and regeneration 5. Here, we identify Sam68 as a distinct target that affords the ability to uniquely regulate CBP mediated transcription in human CSCs. Using a small molecule that targets Sam68, we reveal that shifting its affinity for CBP disrupts CBP/-catenin complexes, leading to immediate changes in histone H3 (K14 and K18) acetylation. Chemical targeting of Sam68 induced global changes in transcriptional programs of patient AML cells involving apoptosis and differentiation and was able to uniquely reduce neoplastic self-renewal of human CSCs in an in vivo model of patient specific acute myeloid leukemia (AML). Our study establishes an approach whereby the CBP/-catenin transcriptome can be uniquely targeted via Sam68 based vulnerability of CSCs that impacts neoplastic differentiation and self-renewal.
Publication Title
Sam68 Allows Selective Targeting of Human Cancer Stem Cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Global gene expression comparison between mesenchymal stem cells (MSCs) purified from the BM of AML patients versus healthy donors.
Publication Title
Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche.
Sample Metadata Fields
Specimen part, Disease stage
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
The composition of chromatin remodeling complexes dictates how these enzymes control transcriptional programs and cellular identity. Here, we investigate the composition of SWI/SNF complexes in embryonic stem cells (ESCs). In contrast to differentiated cells, ESCs have a biased incorporation of certain paralogous SWI/SNF subunits, with low levels of Brm, BAF170 and ARID1B. Upon differentiation, the expression of these subunits increases, resulting in a higher diversity of compositionally distinct SWI/SNF enzymes. We also identify Brd7 as a novel component of the PBAF complex in both ESCs and differentiated cells. Using shRNA-mediated depletion of Brg1, we show that SWI/SNF can function as both a repressor and an activator in pluripotent cells, regulating expression of developmental modifiers and signaling components such as Nodal, ADAMTS1, Bmi-1, CRABP1 and TRH. Knock-down studies of PBAF-specific Brd7 and of a signature subunit within the BAF complex, ARID1A, show that these two sub-complexes affect SWI/SNF target genes differentially, in some cases even antagonistically. This may be due to their different biochemical properties. Finally, we examine the role of SWI/SNF in regulating its target genes during differentiation. We find that SWI/SNF affects recruitment of components of the pre-initiation complex in a promoter-specific manner, to modulate transcription positively or negatively. Taken together, our results provide insight into the function of compositionally diverse SWI/SNF enzymes that underlie their inherent gene-specific mode of action.
Publication Title
BRD7, a novel PBAF-specific SWI/SNF subunit, is required for target gene activation and repression in embryonic stem cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Expression analysis of wild-type SAOS cells and SAOS cells transiently transfected with RB, SMYD2, or RB and SMYD2.
Publication Title
Methylation of the retinoblastoma tumor suppressor by SMYD2.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Saccharomyces cerevisiae
- 24 Downloadable Samples
Illumina HiSeq 2000
Description
The behavior of yeast cells during industrial processes such as the production of beer, wine and bioethanol has been extensively studied. By contrast, our knowledge about yeast physiology during solid state processes, such as bread dough, cheese or cocoa fermentation remains limited. We investigated changes in the transcriptome of three genetically distinct Saccharomyces cerevisiae strains during bread dough fermentation. Our results show that regardless of the genetic background, all three strains exhibit similar changes in expression patterns. At the onset of fermentation, expression of glucose-regulated genes changes dramatically, and the osmotic stress response is activated. The middle fermentation phase is characterized by the induction of genes involved in amino acid metabolism. Finally, at the latest time point, cells suffer from nutrient depletion and activate pathways associated with starvation and stress response. Further analysis shows that genes regulated by the High Osmolarity Glycerol (HOG) pathway, the major pathway involved in the response to osmotic stress and glycerol homeostasis, are among the most differentially expressed genes at the onset of fermentation. More importantly, deletion of HOG1 and other genes of this pathway significantly reduces fermentation capacity. Together, our results demonstrate that cells embedded in a solid matrix such as bread dough suffer severe osmotic stress, and that a proper induction of the HOG pathway is critical for an optimal fermentation.
Publication Title
Dynamics of the Saccharomyces cerevisiae transcriptome during bread dough fermentation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hepatocellular carcinoma (HCC) is a highly prevalent and deadly disease world-wide. The survival of HCC patients is usually very poor due to the lack of efficient anti-cancer drugs
Publication Title
Synthesis and bio-molecular study of (+)-N-Acetyl-α-amino acid dehydroabietylamine derivative for the selective therapy of hepatocellular carcinoma.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- NextSeq 500
Description
Heterochromatic non-coding RNAs induce breast tumor formation in mice by interacting with BRCA1-associated proteins functioning in the DNA damage response. Overall design: mouse tumor mRNA profiles using ribosomal mRNA depletion
Publication Title
Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Inhibition of the costimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage can result in immune suppression. We recently identified small molecule inhibitors that block the interaction between CD40 and TNF Receptor Associated Factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. Here we further characterized the working mechanisms of TRAF-STOPs 6877002 and 6860766 in atherogenesis.
Publication Title
Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis.
Sample Metadata Fields
Specimen part, Treatment
View Samples