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GSE60649
Homo sapiens
9 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF- activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-B to sustain TRAF6/NF-B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.
Publication Title
Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
IlluminaHiSeq2000
Description
CTCF and cohesinSA-1 are regulatory proteins involved in a number of critical cellular processes including transcription, maintenance of chromatin domain architecture, and insulator function. To assess changes in the CTCF and cohesinSA-1 interactomes during erythropoiesis, chromatin immunoprecipitation coupled with high throughput sequencing and mRNA transcriptome analyses via RNA-seq were performed in primary human HSPC hematopoietic stem and progenitor cells (HSPC) and primary human erythroid cells from single donors. Sites of CTCF and cohesinSA-1 co-occupancy were enriched in gene promoters in HSPC and erythroid cells compared to single CTCF or cohesin sites. Cell type-specific CTCF sites in erythroid cells were linked to highly expressed genes, with the opposite pattern observed in HSPCs. Chromatin domains were identified by ChIP-seq with antibodies against trimethylated lysine 27 histone 3, a modification associated with repressive chromatin. Repressive chromatin domains increased in both number and size during hematopoiesis, with many more repressive domains in erythroid cells than HSPCs. CTCF and cohesinSA-1 marked the boundaries of these repressive chromatin domains in a cell-type specific manner. These genomic data support the hypothesis that CTCF and cohesinSA-1 have multiple roles in the regulation of gene expression during erythropoiesis including transcriptional regulation at gene promoters and maintenance of chromatin architecture. Overall design: CD34+-selected stem and progenitor cells were expanded for three days in the absence of EPO. The cells were further cultured in the presence of EPO, and cells differentiated into R3/R4 nucleated erythroid cells. RNA was isolated from three biological replicates of each cell type and sequencing libraries were prepared from poly A selected RNA.
Publication Title
CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Activating mutations of G protein alpha subunits (Ga) occur in 4-5% of all human cancers1 but oncogenic alterations in beta subunits (Gb) have not been defined. Here we demonstrate that recurrent mutations in the Gb proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Ga subunits as well as downstream effectors, and disrupt Ga-Gbg interactions. Different mutations in Gb proteins clustered to some extent based on lineage; for example, all eleven GNB1 K57 mutations were in myeloid neoplasms while 6 of 7 GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 alleles in Cdkn2a-deficient bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K/mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, GNB1 mutations co-occurred with oncogenic kinase alterations, including BCR/ABL, JAK2 V617F and BRAF V600K. Co-expression of patient-derived GNB1 alleles with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 mutations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
Publication Title
Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
Sample Metadata Fields
Cell line, Time
View Samples- Homo sapiens
- 5 Downloadable Samples
- Illumina HiSeq 2000, Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 5 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st), Illumina HiSeq 2000
Description
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism for the induction of granulocytic differentiation and cell death following inhibition of IDH1 mutant protein in primary AML cells, we performed gene expression microarrays following treatment with either GSK321 IDH1 inhibitor or Controls (DMSO or GSK990 inactive inhibitor).
Publication Title
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
Sample Metadata Fields
Specimen part
View Samples- Oryza sativa
- 27 Downloadable Samples
- Affymetrix Rice Genome Array (rice)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Overexpression of a type-A response regulator alters rice morphology and cytokinin metabolism.
Sample Metadata Fields
No sample metadata fields
View Samples- Oryza sativa
- 23 Downloadable Samples
- Affymetrix Rice Genome Array (rice)
Description
Cytokinins (CKs) are a class of plant hormones that regulate many aspects of growth and development, including cell division, apical dominance, leaf senescence, nutrient signaling, and shoot differentiation. In the past decade, substantial progress has been made in understanding CK biosynthesis, metabolism and signal transduction. Much of this knowledge is based on research in Arabidopsis, a dicotyledonous model plant. Although cytokinin plays an important role for growth and development in the Gramineae, our knowledge of cytokinin responsive genes in monocotyledonous species is very limited compared to Arabidopsis. The search for genes whose expression is modified by CK has yielded a number of valuable tools that have been used to understand CK signaling and the complex developmental processes under control of this hormone. We tried to identify rice genes regulated by CK using an Affymetrix rice genome array.
Publication Title
Overexpression of a type-A response regulator alters rice morphology and cytokinin metabolism.
Sample Metadata Fields
No sample metadata fields
View Samples- Oryza sativa
- 4 Downloadable Samples
- Affymetrix Rice Genome Array (rice)
Description
Cytokinins (CKs) are a class of plant hormones that regulate many aspects of growth and development, including cell division, apical dominance, leaf senescence, nutrient signaling, and shoot differentiation. In the past decade, substantial progress has been made in understanding CK biosynthesis, metabolism and signal transduction. Much of this knowledge is based on research in Arabidopsis, a dicotyledonous model plant. The current model of the CK signaling pathway is a multi-step His-Asp phosphorelay system. Some of the cytokinin-inducible response regulators are thought to act as negative regulators of CK signaling. We tried to identify rice genes regulated by CK-inducible response regulator using an Affymetrix rice genome array and transgenic rice that over-express OsRR6.
Publication Title
Overexpression of a type-A response regulator alters rice morphology and cytokinin metabolism.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Sympathetic neurons of SCG (Superior Cervical Ganglia) send axonal projections either along the external carotid arteries to innervate the salivary glands, or along the internal carotid arteries to the lacrimal and pineal glands, the eye, blood vessels and skin of the head, and the mucosa of the oral and nasal cavities. Previous studies using Wnt1Cre and R26R have defined the neural crest and mesodermal origins of vascular smooth muscle in the heart outflow tract and great vessels, although not specifically of the segments that are relevant for the projections of the SCG neurons. The third pharyngeal arch arteries are lined by neural crest-derived smooth muscle, and consequently, their derivatives, including the entirety of the external carotid arteries and only the base of the internal carotid arteries, also have a neural crest origin. In contrast, the dorsal aortae are lined by smooth muscle that is mesodermal in origin, and as a result, the internal carotid arteries from just above their origination from the common carotid arteries have a mesoderm-derived smooth muscle layer. To address the possibility that guidance cues for SCG neurons are selectively expressed by the external carotid vs. the internal carotid arteries, we isolated these segments of the vasculature from mouse embryos at E13.5 and extracted RNA to screen microarrays for differentially expressed genes.
Publication Title
Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons.
Sample Metadata Fields
No sample metadata fields
View Samples- Oryza sativa
- 34 Downloadable Samples
- Affymetrix Rice Genome Array (rice)
Description
Plant hormones interact with each other and regulate gene expression to control plant growth and development. To understand the complex network, accumulation of comprehensive and integrative data of gene expression and hormone concentration is important. Using microarray, global gene expression profile was analyzed to compare with plant hormone concentration in 14 parts of rice at reproductive stage.
Publication Title
UniVIO: a multiple omics database with hormonome and transcriptome data from rice.
Sample Metadata Fields
No sample metadata fields
View Samples