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GSE49120
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
MLL1 translocations encode fusion proteins retaining the N-terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis, thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs), therefore disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B-cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B-cells, menin- or MLL1-regulated genes can be classified into three categories: 1) a relatively small group of co-regulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of 2) exclusively menin-regulated and 3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these two proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1 disrupting drugs as safe and selective leukemia targeting agents.
Publication Title
Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 5 Downloadable Samples
IlluminaGenomeAnalyzerIIx
Description
Comparison of expression profile of Ewing''s sarcoma with cell of origin, mesenchymal stem cells with the goal of identifying novel therapeutic targets. Overall design: 3 Ewing''s cell lines compared to 2 MSC cell lines
Publication Title
Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 64 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genetic studies have shown that human T-ALLs can be divided into subgroups that are characterized by unique gene expression signatures and relate to stages of T-cell differentiation at which the leukemic cells arrest. Each molecular subgroup has characteristic genetic abnormalities that cause aberrant activation of specific T-ALL transcription factor oncogenes, including LYL1/MEF2C, HOXA, TLX1, TLX3 and TAL1/LMO2. Notably, the recently described Early T-cell Precursor ALL (ETP-ALL) patients have leukemic cells that show an early block in T-cell differentiation and significantly overlap with LYL1-positive T-ALL and MEF2C-dysregulated immature T-ALL. We studied the gene expression profiles of 64 primary T-ALL samples and found a high BCL-2 expression in immature T-ALL patients compared to patients belonging to other subgroups.
Publication Title
ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 1 Downloadable Sample
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness.
Sample Metadata Fields
Sex, Disease, Disease stage, Cell line
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Experiments in rodents have shown that kidney ischemia/reperfusion injury (IRI) facilitates lung injury and inflammation. To identify potential ischemia-specific lung molecular pathways involved, we conducted global gene expression profiling of lung 6 or 36 hours following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Total RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n=3/group).
Publication Title
Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 1 Downloadable Sample
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from noninvasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness.
Publication Title
A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness.
Sample Metadata Fields
Sex, Disease, Disease stage, Cell line
View Samples- Homo sapiens
- 138 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Endometriosis, an estrogen-dependent, progesterone-resistant, inflammatory disorder affects 10% of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Since the uterine lining (endometrium) in women with endometriosis has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n=148 archived endometrial samples from women with endometriosis or without endometriosis (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with endometriosis or no endometriosis involved two binary decisions each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no endometriosis from endometriosis, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified endometriosis with 90-100% accuracy, were cycle phase-specific or independent, and utilized relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism and growth factor signaling in endometrium of women with endometriosis. Similar findings were observed with other disorders versus controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic endometriosis with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate-genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of endometriosis and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue.
Publication Title
Molecular classification of endometriosis and disease stage using high-dimensional genomic data.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mammalian digit-tip can regenerate upon amputation1-3, like amphibians. It is unknown why this capacity is limited to the area associated with the nail3-5. Here, we show that nail stem cells (NSCs) reside in the Wnt-suppressed proximal nail matrix and that the mechanisms governing NSC differentiation are directly coupled with their ability of orchestrating digit regeneration. Early nail progenitors located distal to the NCS region undergo Wnt-dependent differentiation into nail. Upon amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to regeneration of the entire digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate nail/digit. Nevertheless, -catenin stabilization in the NSC region induced their regeneration. These results establish a link between NCS differentiation and digit regeneration, suggesting a utility of the NSCs in developing novel treatments for amputees.
Publication Title
Wnt activation in nail epithelium couples nail growth to digit regeneration.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Context: Endometrium in polycystic ovary syndrome (PCOS) presents altered gene expression indicating progesterone resistance and predisposing to reduced endometrial receptivity and endometrial cancer. Objective: We hypothesized that an altered endocrine/metabolic environment in PCOS may result in an endometrial disease phenotype affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny. Design and setting: A prospective study conducted at an academic medical center. Patients and Main Outcome Measures: Proliferative phase endometrium was obtained from 6 overweight/obese PCOS (NIH criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting (FACS)-isolated endometrial epithelial cells (eEP), endothelial cells (eEN), stromal fibroblasts (eSF) and mesenchymal stem cells (eMSC). Gene expression data were validated using microfluidic Q-RT-PCR and immunohistochemistry (IHC). Results: The comparison between eEPPCOS and eEPCtrl showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSFPCOS and eSFCtrl showed upregulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSCPCOS vs. eMSCCtrl the most upregulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). IHC scoring showed increased expression of CCL2 in eEPPCOS and eSFPCOS compared to eEPCtrl and eSFCtrl and IL-6 in eEPPCOS compared to eEPCtrl. Conclusions: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and pro-oncogenic changes, independent of BMI, especially in eEPPCOS and eMSCPCOS, compared to controls. The study reveals an endometrial disease phenotype in women with PCOS with potential negative effects on endometrial function and long-term health.
Publication Title
Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 96 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Comparative analysis of resistant and susceptible macrophage gene expression response to Leishmania major parasite.
Sample Metadata Fields
Specimen part
View Samples