Murine model of gastrointestinal stromal tumors harboring a germline Kit K641E oncogenic mutant
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE12931 | GEO | 2009/09/25
SECONDARY ACCESSION(S): PRJNA110853
REPOSITORIES: GEO
Similar Datasets
Project description:GIST is considered to invariably arise through gain-of-function KIT or PDGFRA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GIST is poorly understood. We analysed the expression levels of 54,613 probe sets in 32 surgical samples of untreated GIST of the stomach and small intestine with GeneChip Human Genome U133 Plus 2.0 arrays. Keywords: gene expression array-based, count
2008-06-15 | GSE8167 | GEO
Project description:GIST is considered to invariably arise through gain-of-function KIT or PDGFRA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GIST is poorly understood. We analysed the expression levels of 54,613 probe sets in 32 surgical samples of untreated GIST of the stomach and small intestine with GeneChip Human Genome U133 Plus 2.0 arrays. Experiment Overall Design: Total RNA was extracted from 32 fresh frozen tumour specimens. We analysed the global gene exprssion profiles of these GIST cases in order to clarify the genomic basis behind the malignant progression of this tumor
2008-10-18 | E-GEOD-8167 | biostudies-arrayexpress
Project description:ETV1 is highly expressed in GIST and their presumed precursors--the interstitial cells of Cajal. ETV1 is required for survival for both GIST and ICC and regulates GIST signature genes. Here, using Illumina-Solexa based next-generation sequencing of ETV1 chromatin immunoprecipates (ChIP-Seq), we define ETV1 binding sites in the GIST48 cell line.
2010-10-14 | GSE22441 | GEO
Project description:Malignant transformation of the interstitial cells of Cajal (ICC) or their precursors gives rise to gastrointestinal stromal tumor (GIST). This mesenchymal neoplasm is characterized by activating mutations in the receptor tyrosine kinases KIT, or other less common mutational subtypes. GIST relies on a highly conserved core transcription factor (TF) network, with expression of accessory disease-state specific TFs. In this study, we define the divergent transcriptional programs supported by accessory TFs HAND1 and BARX1, with HAND1 modulating core TF and KIT gene expression to support GIST cell proliferation. HAND1 was expressed primarily in KIT mutant tumors, including the majority of metastatic tumors or those derived from small bowel, which intrinsically portend a more aggressive clinical course. Assessing archival GIST specimens, HAND1 and BARX1 expression patterns were superior predictors of relapse free survival compared to standard risk stratification. Metastatic tumors expressing HAND1 had a shorter progression free survival on first-line imatinib than those that were HAND1-negative. In contrast, BARX1 expression was enriched in more indolent forms of GIST. Signifying developmental origins of accessory TF expression, HAND1 was expressed solely in ICCs derived from the small intestine, while BARX1 expression was restricted to ICCs of the stomach. These results define the anatomic and transcriptional determinants of GIST clinical phenotypes, and may provide important biomarkers of disease risk stratification in GIST that will inform clinical decision making.
2022-05-23 | GSE151323 | GEO
Project description:Interstitial cells of Cajal (ICC) are electrical pacemakers and mediators of neuromuscular neurotransmission in the gastrointestinal tract. Gastrointestinal stromal tumors (GIST) arise within the ICC lineage due to activating KIT/PDGFRA mutations. In this study we developed a method for isolation of human ICC by immunolabeling and fluorescence-activated cell sorting (FACS). Briefly, human gastric musculature was dissociated and incubated with antibodies against CD45, FCER1A, CD11B, KIT, and CD34. ICC (defined as HP-KIT+CD34- cells), NOT ICC (defined as HP-KIT-CD34- cells), and hematopoietic (HP) cells (defined as HP+ cells) were isolated using FACS. Microarray was performed on ICC, NOT ICC, HP+ cells, and unfractionated gastric tunica muscularis. This study utilized micorarray for the phenotypic characterization of FACS-sorted human ICC, allowing comparison of ICC to other cells of the gastric musculature, including GIST. De-identified human gastric tissues obtained as surgical excess tissue from patients undergoing bariatric operations. This study utilized oligonucleotide microarray analysis to characterize the transcriptome of FACS-sorted human ICC.
2017-02-22 | GSE77839 | GEO
Project description:We report the high-throughput miRNA sequencing of isolated colonic and jejunal Kit+ interstitial cells of Cajal (ICC) from Lepob/ob;KitcopGFP mice, which develop type 2 diabetes, and Lepob/+;KitcopGFP mice which are non-diabetic counterparts and control
2020-12-31 | GSE139578 | GEO
Project description:ETV1 is highly expressed in GIST and their presumed precursors--the interstitial cells of Cajal. ETV1 is required for survival for both GIST and ICC and regulates GIST signature genes. Here, using Illumina-Solexa based next-generation sequencing of ETV1 chromatin immunoprecipates (ChIP-Seq), we define ETV1 binding sites in the GIST48 cell line. Crosslinked ChIP using input control ETV1 ChIP in GIST48 cells. Details: GIST48 cells were crosslinked for 15-minutes in 1% parformaldehyde. Cells were lysed and chromatin sheared using bioruptor. Sheared chromatin was incubated with anti-rabbit IgG dynabeads pre-conjugated with anti-ETV1 antibody (Abcam Ab81086, Lot 787879), washed, eluted, reverse cross-linked, and purified. Purified ChIP DNA was blunt-ended, ligated to Solexa adaptors, amplified with 18-cycles of PCR, and sequenced on Solexa Genome Analyzer. All reads (~36-bp) from ChIP-Seq were aligned to the human genome (build 36, or hg18) using the ELAND alignment software within the Illumina Analysis Pipeline. Unique reads mapped to a single best-matching location with no more than two mismatches were kept and used to generate genome-wide distribution of ETV1-binding and for peak identification. Redundant reads were considered once.
2010-10-14 | E-GEOD-22441 | biostudies-arrayexpress
Project description:Activating mutation of KIT is well known as a key molecular event for the development of gastrointestinal stromal tumors(GISTs). Dysregulation of microRNAs(miRNA) might elucidate KIT mutation, KIT overexpression and the resulting tumorigenesis in GIST. Herein we identified miRNA expression profiles that associated with KIT mutation and KIT overexpression in GIST by miRNA microarrays and Real-time PCR in GISTs. The potentially target genes of selected miRNAs were analyzed by bioinformatic techniques with GO and KEGG pathway analysis. We showed that 6 miRNAs were differentially expressed in CD117IHC+/KITmutant GISTs compared to CD117IHC-/wild-type GISTs. Of these, 2 miRNAs including miR-483-3p and miR-589 were up-regulated, while the other 4 miRNAs including miR-140-5p, miR-148b-3p, miR-1587 and miR-4507 were down-regulated. GO and KEGG analysis demonstrated that miRNAs with significant change were involved in regulation of target genes related to the development of GIST. Among the candidate miRNAs studied, miR-148b-3p and miR-140-5p may be involved in GIST tumorigenesis via targeting mutant KIT or via intermediate molecules of PDGFRA, PI3K-AKT and MAPK pathway, such as AKT2, MAPK1, MAPK10, STAT5A, SMAD4, SMAD5 and PTEN. Furthermore, the reduced expression of miR-140-5p and miR-148b-3p were inversely correlated with high-risk grade, recurrence and metastasis of GIST. The current findings indicated that miR-148b-3p and miR-140-5p were not only involved in tumorigenesis of GIST, but might also participate in the progression of GIST and could be considered as novel biomarkers for potentially predicting the prognosis of GIST.
2018-04-25 | GSE73346 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.
2019-01-23 | GSE113215 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.
2019-01-23 | GSE113207 | GEO