Defining the impact of mutant oncogene zygosity
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PROVIDER: PRJNA853441 | ENA |
REPOSITORIES: ENA
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Project description:Defining the impact of mutant oncogene zygosity
| PRJNA853444 | ENA
Project description:Oncogene addiction to GNAS in GNASR201 mutant tumors
| PRJNA859019 | ENA
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
2015-12-23 | GSE70991 | GEO
Project description:Defining the impact of exoribonucleases in the shift between exponential and stationary phases
| PRJNA482775 | ENA
Project description:Mutant TP53, mutant KRAS and hyperactive CMYC are driver oncogenes with no standard clinical protocols for their direct targeting. To identify interplay of mutant TP53, KRAS and hyperactive CMYC, and exploit them in a therapeutic manner, we performed global proteomics and transcriptomics in a panel of 8 cell lines of colorectal and lung cancers 48h post knock-out of the oncogenes with CRISPR/Cas9. In each cancer type the cell lines containing either all, or one, of each of the activated oncogenes were analyzed. Higher numbers of significant protein and transcript level changes were observed upon CMYC and KRAS disruption compared to mutant TP53 disruption. In contrast to mutant KRAS and CMYC downstream programs the number of mutant p53-dependent proteins and transcripts was reduced several-fold in the presence of mutant KRAS and hyperactive CMYC, compared to cell lines with mutant p53 only. We observed a functional repression of the mutant p53 ability to drive phenotype of cancer cells and transcriptional activity in the presence of mutated KRAS and/or overexpressed CMYC, which in such configuration overtake many of the mutant p53 functions. An overlap of pathways regulated by the transcripts and proteins revealed a molecular program shared by the oncogenes as well as pathways lost or retained in the mutant p53 program, when co-present with the other oncogenes. This allowed to exploit the program common to the oncogenes by experimental, pre-clinical drug targeting. Oncogene cooperation is known to be important in driving cell transformation, however our observations suggest that mutant KRAS and/or overexpressed CMYC compete with mutant p53 for activation of important oncogenic pathways. While the exact mechanism of this competition is under investigation, we hypothesize that mutant p53 is a context-dependent oncogene – whose gain-of-function range of impact heavily depends on the molecular background of neoplastic cells.
2024-08-31 | GSE239817 | GEO
Project description:We designed two different BCL2 deregulation models in transgenic mice, whereby the oncogene was either associated with the IgH3′RR superenhancer, as in t(14;18), or inserted into the kappa light chain locus. We compared the impact of these models on B-cell fate and lymphoid tissues. Linkage to the IgH superenhancer showed a quite specific impact on germinal center B cell populations. The Ig kappa model was much less specific and strongly boosted the plasma cell in-flow and the accumulation of long-lived plasma cells.
2022-11-10 | GSE217605 | GEO
Project description:We designed two different BCL2 deregulation models in transgenic mice, whereby the oncogene was either associated with the IgH3′RR superenhancer, as in t(14;18), or inserted into the kappa light chain locus. We compared the impact of these models on B-cell fate and lymphoid tissues. Linkage to the IgH superenhancer showed a quite specific impact on germinal center B cell popu-lations. The Ig kappa model was much less specific and strongly boosted the plasma cell in-flow and the accumulation of long-lived plasma cells.
2022-11-07 | GSE217095 | GEO
Project description:The GNASR201 gain-of-function mutation is the single most frequent cancer-causing mutation across all heterotrimeric G proteins, driving oncogenesis in various low-grade/benign gastrointestinal and pancreatic tumors. In this study, we investigated the role of GNAS and its product Gαs in tumor progression using peritoneal models of colorectal cancer (CRC). GNAS was knocked out in multiple CRC cell lines harboring GNASR201C/H mutations (KM12, SNU175, SKCO1), leading to decreased cell-growth in 2D and 3D organoid models. Nude mice were peritoneally injected with GNAS-knockout KM12 cells, leading to a decrease in tumor growth and drastically improved survival at 7 weeks. Supporting these findings, GNAS overexpression in LS174T cells led to increased cell-growth in 2D and 3D organoid models, and increased tumor growth in PDX mouse models. GNAS knockout decreased levels of cyclic AMP in KM12 cells, and molecular profiling identified phosphorylation of β-catenin and activation of its targets as critical downstream effects of mutant GNAS signaling. Supporting these findings, chemical inhibition of both PKA and β-catenin reduced growth of GNAS mutant organoids. Our findings demonstrate oncogene addiction to GNAS in peritoneal models of GNASR201C/H tumors, which signal through the cAMP/PKA and Wnt/β-catenin pathways. Thus, GNAS and its downstream mediators are promising therapeutic targets for GNAS mutant tumors.
2022-07-19 | GSE208278 | GEO
Project description:Mechanism of Oncogene Addiction
| PRJNA302297 | ENA