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Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma

Author

Listed:
  • Michelle M. Kameda-Smith

    (McMaster University
    McMaster University
    McMaster University)

  • Helen Zhu

    (Computational Biology Program, Ontario Institute for Cancer Research
    University of Toronto
    University Health Network
    Vector Institute Toronto)

  • En-Ching Luo

    (University of California at San Diego
    Stem Cell Program, University of California San Diego
    Sanford Consortium for Regenerative Medicine)

  • Yujin Suk

    (McMaster University
    McMaster University
    McMaster University)

  • Agata Xella

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Brian Yee

    (University of California at San Diego
    Stem Cell Program, University of California San Diego
    Sanford Consortium for Regenerative Medicine)

  • Chirayu Chokshi

    (McMaster University
    McMaster University)

  • Sansi Xing

    (McMaster University
    McMaster University)

  • Frederick Tan

    (University of California at San Diego
    Stem Cell Program, University of California San Diego
    Sanford Consortium for Regenerative Medicine)

  • Raymond G. Fox

    (University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine)

  • Ashley A. Adile

    (McMaster University
    McMaster University)

  • David Bakhshinyan

    (McMaster University
    McMaster University)

  • Kevin Brown

    (University of Toronto)

  • William D. Gwynne

    (McMaster University
    McMaster University)

  • Minomi Subapanditha

    (McMaster University)

  • Petar Miletic

    (McMaster University
    McMaster University)

  • Daniel Picard

    (University Hospital Düsseldorf)

  • Ian Burns

    (McMaster University)

  • Jason Moffat

    (University of Toronto)

  • Kamil Paruch

    (Masaryk University
    International Clinical Research Center, St. Anne’s University Hospital in Brno)

  • Adam Fleming

    (McMaster University, Departments of Pediatrics, Hematology and Oncology Division)

  • Kristin Hope

    (McMaster University
    McMaster University)

  • John P. Provias

    (McMaster University, Departments of Neuropathology)

  • Marc Remke

    (University Hospital Düsseldorf)

  • Yu Lu

    (McMaster University
    McMaster University)

  • Tannishtha Reya

    (University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine
    Columbia University Medical Center)

  • Chitra Venugopal

    (McMaster University
    McMaster University)

  • Jüri Reimand

    (Computational Biology Program, Ontario Institute for Cancer Research
    University of Toronto
    Department of Molecular Genetics, University of Toronto)

  • Robert J. Wechsler-Reya

    (Sanford Burnham Prebys Medical Discovery Institute
    Columbia University Medical Center)

  • Gene W. Yeo

    (University of California at San Diego
    Stem Cell Program, University of California San Diego
    Sanford Consortium for Regenerative Medicine)

  • Sheila K. Singh

    (McMaster University
    McMaster University
    McMaster University
    McMaster University, Department of Pediatrics)

Abstract

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Suggested Citation

  • Michelle M. Kameda-Smith & Helen Zhu & En-Ching Luo & Yujin Suk & Agata Xella & Brian Yee & Chirayu Chokshi & Sansi Xing & Frederick Tan & Raymond G. Fox & Ashley A. Adile & David Bakhshinyan & Kevin , 2022. "Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35118-3
    DOI: 10.1038/s41467-022-35118-3
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