دورية أكاديمية
أعرض في EDS

A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.

التفاصيل البيبلوغرافية
العنوان: A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.
المؤلفون: Saulnier O; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.; Genomics and Development of Childhood Cancers, Institut Curie, PSL University, Paris, France.; INSERM U830, Cancer, Heterogeneity, Instability and Plasticity, Institut Curie, PSL University, Paris, France.; SIREDO Oncology Center, Institut Curie, Paris, France., Zagozewski J; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Liang L; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Hendrikse LD; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Layug P; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Gordon V; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Aldinger KA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA., Haldipur P; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Borlase S; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Coudière-Morrison L; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Cai T; Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.; Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada., Martell E; Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.; Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Gonzales NM; Texas Children's Hospital, Houston, TX, USA.; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA., Palidwor G; Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., Porter CJ; Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., Richard S; Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.; Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada., Sharif T; Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.; Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Millen KJ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA., Doble BW; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.; Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada., Taylor MD; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. mdt.cns@gmail.com.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. mdt.cns@gmail.com.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. mdt.cns@gmail.com.; Texas Children's Hospital, Houston, TX, USA. mdt.cns@gmail.com.; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA. mdt.cns@gmail.com.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. mdt.cns@gmail.com.; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. mdt.cns@gmail.com.; Texas Children's Cancer and Hematology Center, Houston, TX, USA. mdt.cns@gmail.com.; Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA. mdt.cns@gmail.com.; Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA. mdt.cns@gmail.com.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. mdt.cns@gmail.com., Werbowetski-Ogilvie TE; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Tamra.Ogilvie@bcm.edu.; Texas Children's Hospital, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.; Texas Children's Cancer and Hematology Center, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.
المصدر: Nature cell biology [Nat Cell Biol] 2024 Aug; Vol. 26 (8), pp. 1233-1246. Date of Electronic Publication: 2024 Jul 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Macmillan Magazines Ltd Country of Publication: England NLM ID: 100890575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4679 (Electronic) Linking ISSN: 14657392 NLM ISO Abbreviation: Nat Cell Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Macmillan Magazines Ltd., [1999-
مواضيع طبية MeSH: Otx Transcription Factors*/metabolism , Otx Transcription Factors*/genetics , Medulloblastoma*/genetics , Medulloblastoma*/pathology , Medulloblastoma*/metabolism , Alternative Splicing*/genetics , Neoplastic Stem Cells*/metabolism , Neoplastic Stem Cells*/pathology , Cerebellar Neoplasms*/genetics , Cerebellar Neoplasms*/pathology , Cerebellar Neoplasms*/metabolism, Humans ; Animals ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Mice ; Cell Proliferation
مستخلص: OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression.
(© 2024. The Author(s).)
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معلومات مُعتمدة: R01 CA159859 United States CA NCI NIH HHS; R01 CA255369 United States CA NCI NIH HHS; R01 NS106155 United States NS NINDS NIH HHS; R37 NS095733 United States NS NINDS NIH HHS
المشرفين على المادة: 0 (Otx Transcription Factors)
0 (OTX2 protein, human)
0 (Otx2 protein, mouse)
تواريخ الأحداث: Date Created: 20240718 Date Completed: 20240813 Latest Revision: 20240816
رمز التحديث: 20240816
مُعرف محوري في PubMed: PMC11321995
DOI: 10.1038/s41556-024-01460-5
PMID: 39025928
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4679
DOI:10.1038/s41556-024-01460-5