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A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M I

ABSTRACT: Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is increased when tumorigenesis is initiated in Nestin+ cells. Therefore, we need to find how the tumorigenic effects of H3.3K27M are more oncogenic in Nestin+ cells than Olig2+ cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE184934 | GEO | 2021/10/05

REPOSITORIES: GEO

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A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M III

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-B overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184936 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M II

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184935 | GEO

RNAseq analysis of murine brainstem gliomas with and without H3.3K27M

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2017-05-11 | GSE98765 | GEO

Candidate pathways for promoting differentiation and quiescence of oligodendrocyte progenitor-like cells in glioblastoma

2012-10-04 | GSE30626 | GEO

Candidate pathways for promoting differentiation and quiescence of oligodendrocyte progenitor-like cells in glioblastoma

Project description:The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence. There are two datasets here. One characterizes the normal translational profiles of neurons, astrocytes, mature and immature oligodendrocytes. Each cell type was profiled in triplicate, from pools of at least two mice, and total RNA controls were collected in parallel. The second dataset includes translational profiles of Olig2 positive cells from tumors form several variations of a murine model of glioma. Each variation was collected at least in triplicate, and total RNA controls were analyzed in parallel. All translational profiles were generated using the Translating Ribosome Affinity Purification protocol.

2012-10-04 | E-GEOD-30626 | biostudies-arrayexpress

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2021-08-05 | GSE135417 | GEO

Epigenome programming by H3.3K27M mutation creates a dependence of pediatric glioma on SMARCA4

Project description:Patients with diffuse midline gliomas-H3K27-altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 co-localizes with SOX10 at gene regulatory elements (GRE) to control the expression of genes involved in cell growth and extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG.

2022-09-02 | GSE185280 | GEO

Generation of oligodendroglial cells by direct lineage conversion

Project description:We report the generation of induced oligodendrocyte precursor cells (iOPCs) by direct lineage conversion. Forced expression of the three transcription factors Sox10, Olig2 and Zfp536 was sufficient to convert mouse and rat fibroblasts into iOPCs with morphologies and gene expression signatures that resemble OPCs. We compared the global gene expression pattern of iOPCs, fibroblasts, primary OPCs from the neonatal rat brain, and their differentiated progeny. We purified iOPCs by O4 immunopanning three weeks after infection and extracted total RNA. Acutely isolated rat cortical OPCs were either used directly for RNA extraction or expanded in mitogen-containing media for 24h before switching into differentiation medium, lacking PDGF/NT-3 and containing T3. Cells were harvested for microarray analysis 3 and 6 days after induction of differentiation.

2013-04-07 | E-GEOD-40421 | biostudies-arrayexpress

Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model. In order to generate DIPG‐bearing mice, we are using the RCAS/Tv‐a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells‐of‐origin using transgenic Tv‐a‐expressing mice (Tv‐a being the receptor for RCAS viruses). We injected P3‐P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS‐PDGF‐A + RCAS‐H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy.

2021-09-28 | GSE184786 | GEO

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2023-03-10 | PXD036975 | Pride

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