Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation
Open accessAbstract
Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice.
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Human embryonic stem cell-derived neural progenitor cells transduced with H3.3K27M, p53 shRNA and mutant PDGFRAD842V transformed only after months of in vitro passaging and produced low-grade glioma, not high-grade glioma, when transplanted into immunocompromised mice.
“A recent study reported that transduction of human embryonic stem cell-derived NPCs with H3.3K27M, p53 shRNA and constitutively active, mutant PDGFRAD842V led to neoplastic transformation, but only via in vitro passaging over several months (Funato et al., 2014). Furthermore, when transplanted into recipient immunocompromised mice, these genetically modified NPCs gave rise exclusively to low-grade”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Funato et al., 2014
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References 30 · Cited by 390
- Authors
- Funato, K., Major, T., Lewis, P. W., Allis, C. D., & Tabar, V.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Wisconsin–Madison (US)
- Rockefeller University (US)
- Corresponding author
- Tabar, Viviane
- Venue
- Science
- Published
- 2014-12-19
- Volume
- 346
- Issue
- 6216
- Pages
- 1529-1533
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4995593
- OpenAlex
- W2048546023
- Cited by
- 390
- References
- 30
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 27 · 2023: 40 · 2022: 28 · 2021: 42 · 2020: 37 · 2019: 44 · 2018: 36 · 2017: 42 · 2016: 32 · 2015: 24 · 2014: 2
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- diffuse intrinsic pontine glioma, pediatric glioma, H3.3K27M mutation, histone H3.3, human embryonic stem cells, neural progenitor cells, p53 deficiency, oncogenic transformation, histone modifications, menin, drug screening, brainstem tumors
- MeSH terms
- Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Child, Drug Screening Assays, Antitumor, Glioma, Histones, Humans, Models, Genetic, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Brain Stem Neoplasms, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Genome-Wide Association Study, Neural Stem Cells
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