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    Science (New York, N.Y.). pii: 360/6386/331. doi: 10.1126/science.aao4750
    Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.
    Filbin MG1,  Tirosh I2,  Hovestadt V3,  Shaw ML4,  Escalante LE5,  Mathewson ND6,  Neftel C7,  Frank N8,  Pelton K9,  Hebert CM10,  Haberler C11,  Yizhak K12,  Gojo J13,  Egervari K14,  Mount C15,  van Galen P16,  Bonal DM17,  Nguyen QD18,  Beck A19,  Sinai C20,  Czech T21,  Dorfer C22,  Goumnerova L23,  Lavarino C24,  Carcaboso AM25,  Mora J26,  Mylvaganam R27,  Luo CC28,  Peyrl A29,  Popović M30,  Azizi A31,  Batchelor TT32,  Frosch MP33,  Martinez-Lage M34,  Kieran MW35,  Bandopadhayay P36,  Beroukhim R37,  Fritsch G38,  Getz G39,  Rozenblatt-Rosen O40,  Wucherpfennig KW41,  Louis DN42,  Monje M43,  Slavc I44,  Ligon KL45,  Golub TR46,  Regev A47,  Bernstein BE48,  Suvà ML49
    Author information
    1Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    2Klarman Cell Observatory, Broad Institute of Harvard and Massachussetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
    3Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    4Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    5Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    6Department of Cancer Immunology and Virology, Department of Microbiology and Immunobiology, Department of Neurology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
    7Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    8Children's Cancer Research Institute (CCRI), St. Anna Kinderspital, Medical University of Vienna, Vienna, Austria.
    9Department of Oncologic Pathology, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
    10Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    11Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    12Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
    13Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
    14Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    15Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
    16Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    17Center for Biomedical Imaging in Oncology, Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
    18Center for Biomedical Imaging in Oncology, Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
    19Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    20Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    21Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
    22Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
    23Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    24Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.
    25Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.
    26Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.
    27Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    28Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    29Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
    30Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
    31Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
    32Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
    33Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    34Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    35Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    36Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    37Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
    38Children's Cancer Research Institute (CCRI), St. Anna Kinderspital, Medical University of Vienna, Vienna, Austria.
    39Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    40Klarman Cell Observatory, Broad Institute of Harvard and Massachussetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
    41Department of Cancer Immunology and Virology, Department of Microbiology and Immunobiology, Department of Neurology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
    42Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    43Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
    44Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
    45Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    46Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
    47Klarman Cell Observatory, Broad Institute of Harvard and Massachussetts Institute of Technology (MIT), Cambridge, MA 02142, USA. suva.mario@mgh.harvard.edu bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org.
    48Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. suva.mario@mgh.harvard.edu bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org.
    49Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. suva.mario@mgh.harvard.edu bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org.
    Abstract

    Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.


    Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

    Publikations ID: 29674595
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