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A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.
Saulnier, Olivier; Zagozewski, Jamie; Liang, Lisa; Hendrikse, Liam D; Layug, Paul; Gordon, Victor; Aldinger, Kimberly A; Haldipur, Parthiv; Borlase, Stephanie; Coudière-Morrison, Ludivine; Cai, Ting; Martell, Emma; Gonzales, Naomi M; Palidwor, Gareth; Porter, Christopher J; Richard, Stéphane; Sharif, Tanveer; Millen, Kathleen J; Doble, Brad W; Taylor, Michael D; Werbowetski-Ogilvie, Tamra E.
Affiliation
  • Saulnier O; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Zagozewski J; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Liang L; Genomics and Development of Childhood Cancers, Institut Curie, PSL University, Paris, France.
  • Hendrikse LD; INSERM U830, Cancer, Heterogeneity, Instability and Plasticity, Institut Curie, PSL University, Paris, France.
  • Layug P; SIREDO Oncology Center, Institut Curie, Paris, France.
  • Gordon V; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Aldinger KA; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Haldipur P; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Borlase S; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Coudière-Morrison L; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Cai T; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Martell E; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Gonzales NM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • Palidwor G; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
  • Porter CJ; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
  • Richard S; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • Sharif T; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Millen KJ; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Doble BW; Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
  • Taylor MD; Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
  • Werbowetski-Ogilvie TE; Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Nat Cell Biol ; 26(8): 1233-1246, 2024 Aug.
Article in En | MEDLINE | ID: mdl-39025928
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplastic Stem Cells / Cerebellar Neoplasms / Alternative Splicing / Otx Transcription Factors / Medulloblastoma Limits: Animals / Humans Language: En Journal: Nat Cell Biol Year: 2024 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplastic Stem Cells / Cerebellar Neoplasms / Alternative Splicing / Otx Transcription Factors / Medulloblastoma Limits: Animals / Humans Language: En Journal: Nat Cell Biol Year: 2024 Document type: Article Affiliation country: Country of publication: