Human ESC-based modeling of H3.3G34R-mutant high grade glioma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147543 | GEO | 2021/02/25
REPOSITORIES: GEO
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Project description:Human ESC-based modeling of H3.3G34R-mutant high grade glioma
| PRJNA615218 | ENA
Project description:The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location since SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high level SHH signaling compared to GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide new insights into intrinsic differences within GCPs that impact on SHH-MB progression.
2018-02-22 | GSE110932 | GEO
Project description:H3.3G34R/V hemispheric gliomas carrya dismal prognosisas current treatments including radio/chemotherapy are not curative. We undertook a systematic and comprehensive epigenetic approach to define therapeutic dependenciesin H3.3G34R/V gliomas.
2021-12-15 | GSE161288 | GEO
Project description:H3.3G34R/V hemispheric gliomas carry a dismal prognosis as current treatments including radio/chemotherapy are not curative. We undertook a systematic and comprehensive epigenetic approach to define therapeutic dependencies in H3.3G34R/V gliomas.
2021-12-15 | GSE161287 | GEO
Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets. Human ES cells were differentiated to NPCs and lentivirally transduced with a combination of constitutively active PDGFRA (D842V), sh-p53, and WT or K27M mutant form of histone H3.3 variant.
2014-11-21 | E-GEOD-55541 | biostudies-arrayexpress
Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets.
2014-11-21 | GSE55541 | GEO
Project description:Histone H3 point mutations have recently been identified in pediatric brain cancers, including missense mutations on histone H3 at positions 27 (lysine to methionine; K27M) and 34 (glycine to arginine, G34R), respectively. H3K27M mutations are associated with a majority of pediatric Diffuse Intrinsic Pontine Pediatric Glioma (DIPG) cases, while H3.3G34R is found in pediatric glioblastoma (GBM) arising in the cerebral cortex1,2. While the mechanisms of H3K27M-driven tumorigenesis are beginning to unravel, much less is known about the H3.3G34R mutation. Here, we provide both biochemical and structural evidence that the PHD (plant homedomain) domain of the enhancer-binding protein, RACK7 (ZMYND8), recognizes H3.3G34R mutant histone via a mechanism distinct from other PHD domains. In an H3.3G34R-expressing neuronal precursor cell line, we demonstrate that RACK7 is aberrantly recruited to enhancers bound by H3.3G34R, resulting in the down-regulation of many neuronal genes, and the up-regulation of oncogenes such as MYC. Neural precursor cells expressing H3.3G34R showed enhanced tumor growth when injected subcutaneously. Inhibiting RACK7 binding to H3.3G34R reduces tumor size and alters gene expression, suggesting that H3.3G34R regulation of enhancers via RACK7 promotes tumorigenesis. Specifically, we show that both the gene expression and tumor size regulation are critically dependent on the physical interaction of H3.3G34R with RACK7. Both regulations are compromised in the absence of RACK7, and can be rescued by wildtype, but not an H3.3G34R-binding defective, RACK7. Taken together, we have identified a reader for H3.3G34R and demonstrate that RACK7 binding to H3.3G34R alters enhancer activity to directly suppress neural gene transcription and to increase oncogenic propensity of neural precursor cells, thus providing a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.
2024-04-14 | GSE99979 | GEO
Project description:Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n = 83) and show that ~50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain, expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumors entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to terminally differentiate, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.
2020-11-30 | GSE146731 | GEO
Project description:Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities—H3.3G34R/PDGFRAC235Yto FGFR inhibition, H3.3K27M/PDGFRAWTto PDGFRA inhibition, and H3.3K27M/PDGFRAWTand H3.3K27M/PPM1DΔC/PIK3CAE545Kto combined inhibition of MEK and PIK3CA. Moreover, H3.3K27Mtumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.
2023-09-12 | GSE242998 | GEO
Project description:Mouse model with P53f/f;Nf1f/+;Ptenf/+ configuration driven by Nestin-creERT2 and NG2-creERTM induced at 1 month postnatal forms high grade glioma in the brain. Tumors were harvested and total RNA were extracted for gene expression profile. Three tumors were harvested from the Nestin-creERT2 mouse model and 5 tumors were harvested from the NG2-creERTM mouse model with desired genotype when mice show neurological symptomes. Three control brain tissue for each model were harvested at corresponding anatomical position in the control mice. Total RNA were extracted from the tumor tissue and control tissue
2015-07-30 | E-GEOD-57038 | biostudies-arrayexpress