Publication Date:
2014-12-20
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Funato, Kosuke -- Major, Tamara -- Lewis, Peter W -- Allis, C David -- Tabar, Viviane -- New York, N.Y. -- Science. 2014 Dec 19;346(6216):1529-33. doi: 10.1126/science.1253799. Epub 2014 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. ; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA. ; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525250" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antineoplastic Agents/pharmacology
;
Brain Stem Neoplasms/*genetics/pathology
;
Cell Transformation, Neoplastic/*genetics/pathology
;
Child
;
Drug Screening Assays, Antitumor
;
Embryonic Stem Cells/*metabolism/pathology
;
Epigenesis, Genetic
;
Gene Expression Regulation, Neoplastic
;
Genome-Wide Association Study
;
Glioma/*genetics/pathology
;
Histones/*genetics
;
Humans
;
Mice
;
*Models, Genetic
;
Neural Stem Cells/*metabolism/pathology
;
Proto-Oncogene Proteins/antagonists & inhibitors
;
Tumor Suppressor Protein p53/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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