title: Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Funato
authors.affiliation: Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Major
authors.affiliation: Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.affiliation: Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. tabarv@mskcc.org.
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002648:Child; D004354:Drug Screening Assays, Antitumor; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53