PATH-09. SUBTYPE-ASSOCIATED RNA SPLICING CONTROLLED BY GLIOMA DRIVER MUTATIONS REGULATES GLIOMAGENESIS. (14th November 2022)

• Record Type: Journal Article
• Authors: Song, Xiao; Huang, Tianzhi; Tiek, Deanna; Miki, Shunichiro; Goenka, Anshika; Iglesia, Rebeca; Furnari, Frank; Hu, Bo; Hu, Bo
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii151
• Page End: vii151
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.582
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Dysregulated RNA alternative splicing (AS) is a hallmark of cancer and has been studied in cancers including glioma. However, whether the dysregulated AS and the regulating RNA-binding proteins (RBPs) drive gliomagenesis and the role of glioma driver mutations in shaping the RBP/AS landscape have not been studied. Here we describe two AS-defined glioma subtypes that correlate with IDH1 mutation, tumor grade, and patient prognosis. Oncogenic AS isoforms are exclusively associated with AS subtype 2, IDH1 wild-type gliomas. Modulation of representative AS isoforms or subtype-associated RBPs regulate glioma stem-like cell (GSC) tumorgenicity. With a human induced pluripotent stem cell-derived glioma model system, we demonstrate that specific glioma driver mutations are involved in shaping the subtype-associated AS. Lastly, we target a sub2-associated RBP with anti-sense oligonucleotides to inhibit GSC tumorigenicity. Our data establish relationships between glioma driver mutations and AS programs and identify dysregulated RBP/AS network as a therapeutic vulnerability.