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PPM1D is a neurobla...
PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors
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- Milosevic, Jelena (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
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- Fransson, Susanne (författare)
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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- Gulyas, Miklos, MD, PhD, Associate Professor, 1959- (författare)
- Uppsala universitet,Klinisk och experimentell patologi
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- Gallo-Oller, Gabriel (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Olsen, Thale K (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Treis, Diana (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Wickström, Malin (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Elfman, Lotta HM (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Sveinbjornsson, Baldur (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Department of Medical Biology, University of Tromsö, Tromsö, Norway
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- Hertwig, Falk (författare)
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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- Bartenhagen, Christoph (författare)
- Department of Experimental Pediatric Oncology, University Children’s Hospital, Cologne, Germany; Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
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- Reinsbach, Susanne (författare)
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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- Wilhelm, Margareta (författare)
- Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm, Sweden
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- Abel, Frida (författare)
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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- Javanmardi, Niloufar (författare)
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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- Thankaswamy-Kosalai, Subazini (författare)
- Department of Medical Genetics and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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- Eissler, Nina (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Kock, Anna (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Shi, Yao (författare)
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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- Tanino, Keiji (författare)
- Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan
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- Hehir-Kwa, Jane Y (författare)
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Mensenkamp, Arjen (författare)
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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- Tytgat, Godelieve AM (författare)
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Kanduri, Chandrasekhar (författare)
- Department of Medical Genetics and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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- Holmberg, Johan (författare)
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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- Gisselsson, David (författare)
- Department of Genetics and Pathology, University of Lund, Lund, Sweden
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- Molenaar, Jan J (författare)
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Jongmans, Marjolijn (författare)
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Fischer, Matthias (författare)
- Department of Experimental Pediatric Oncology, University Children’s Hospital, Cologne, Germany; Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
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- Kool, Marcel (författare)
- Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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- Sakaguchi, Kazuyasu (författare)
- Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan
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- Baryawno, Ninib (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, USA
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- Martinsson, Tommy (författare)
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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- Johnsen, John Inge (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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- Kogner, Per (författare)
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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(creator_code:org_t)
- Cold Spring Harbor Laboratory, 2020
- Engelska.
- Relaterad länk:
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https://doi.org/10.1...
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http://biorxiv.org/c...
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https://uu.diva-port... (primary) (Raw object)
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http://uu.diva-porta...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
Nyckelord
- Patologi
- Pathology
Publikations- och innehållstyp
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- Av författaren/redakt...
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Milosevic, Jelen ...
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Fransson, Susann ...
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Gulyas, Miklos, ...
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Gallo-Oller, Gab ...
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Olsen, Thale K
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Treis, Diana
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visa fler...
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Wickström, Malin
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Elfman, Lotta HM
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Sveinbjornsson, ...
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Hertwig, Falk
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Bartenhagen, Chr ...
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Reinsbach, Susan ...
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Wilhelm, Margare ...
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Abel, Frida
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Javanmardi, Nilo ...
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Thankaswamy-Kosa ...
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Eissler, Nina
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Kock, Anna
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Shi, Yao
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Tanino, Keiji
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Hehir-Kwa, Jane ...
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Mensenkamp, Arje ...
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Tytgat, Godeliev ...
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Kanduri, Chandra ...
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Holmberg, Johan
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Gisselsson, Davi ...
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Molenaar, Jan J
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Jongmans, Marjol ...
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Fischer, Matthia ...
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Kool, Marcel
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Sakaguchi, Kazuy ...
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Baryawno, Ninib
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Martinsson, Tomm ...
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Johnsen, John In ...
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Kogner, Per
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Klinisk laborato ...
- Av lärosätet
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Uppsala universitet