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

MM. Kameda-Smith, H. Zhu, EC. Luo, Y. Suk, A. Xella, B. Yee, C. Chokshi, S. Xing, F. Tan, RG. Fox, AA. Adile, D. Bakhshinyan, K. Brown, WD. Gwynne, M. Subapanditha, P. Miletic, D. Picard, I. Burns, J. Moffat, K. Paruch, A. Fleming, K. Hope, JP....

. 2022 ; 13 (1) : 7506. [pub] 20221206

Language English Country England, Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22032233

Grant support
T32 HL086344 NHLBI NIH HHS - United States
T32 CA009523 NCI NIH HHS - United States

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.

Centre for Discovery in Cancer Research McMaster University Hamilton ON Canada

Computational Biology Program Ontario Institute for Cancer Research Toronto Canada

Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada

Department of Cellular and Molecular Medicine University of California at San Diego La Jolla CA USA

Department of Chemistry CZ Openscreen Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Medical Biophysics University of Toronto Toronto Canada

Department of Molecular Genetics University of Toronto Toronto Canada

Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty University Hospital Düsseldorf Düsseldorf Germany

Departments of Pharmacology and Medicine University of California San Diego School of Medicine Sanford Consortium for Regenerative Medicine La Jolla CA USA

Donnelly Centre Department of Molecular Genetics University of Toronto Toronto Canada

Herbert Irving Comprehensive Cancer Center Department of Physiology and Cellular Biophysics Columbia University Medical Center New York NY USA

International Clinical Research Center St Anne's University Hospital in Brno 602 00 Brno Czech Republic

McMaster University Department of Pediatrics Hamilton Canada

McMaster University Departments of Neuropathology Hamilton Canada

McMaster University Departments of Pediatrics Hematology and Oncology Division Hamilton Canada

Michael G DeGroote School of Medicine McMaster University Hamilton Canada

Sanford Consortium for Regenerative Medicine La Jolla CA USA

Stem Cell Program University of California San Diego La Jolla CA USA

Surgery Faculty of Health Sciences McMaster University Hamilton ON Canada

Tumor Initiation and Maintenance Program National Cancer Institute Designated Cancer Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA

University Health Network Toronto ON Canada

Vector Institute Toronto Toronto ON Canada

References provided by Crossref.org

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