A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Sin-Chan, Patrick; Mumal, Iqra; Suwal, Tannu; Ho, Ben; Fan, Xiaolian; Singh, Irtisha; Du, Yuchen; Lu, Mei; Patel, Neilket; Torchia, Jonathon; Popovski, Dean; Fouladi, Maryam; Guilhamon, Paul; Hansford, Jordan R.; Leary, Sarah; Hoffman, Lindsey M.; Mulcahy Levy, Jean M.; Lassaletta, Alvaro; Solano-Paez, Palma; Rivas, Eloy; Reddy, Alyssa; Gillespie, G. Yancey; Gupta, Nalin; Van Meter, Timothy E.; Nakamura, Hideo; Wong, Tai-Tong; Ra, Young-Shin; Kim, Seung-Ki; Massimi, Luca; Grundy, Richard G.; Fangusaro, Jason; Johnston, Donna; Chan, Jennifer; Lafay-Cousin, Lucie; Hwang, Eugene I.; Wang, Yin; Catchpoole, Daniel; Michaud, Jean; Ellezam, Benjamin; Ramanujachar, Ramya; Lindsay, Holly; Taylor, Michael D.; Hawkins, Cynthia E.; Bouffet, Eric; Jabado, Nada; Singh, Sheila K.; Kleinman, Claudia L.; Barsyte-Lovejoy, Dalia; Li, Xiao-Nan; Dirks, Peter B.; Lin, Charles Y.; Mack, Stephen C.; Rich, Jeremy N.; Huang, Annie

Abstract

© 2019 Elsevier Inc. Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.

Citation

Sin-Chan, P., Mumal, I., Suwal, T., Ho, B., Fan, X., Singh, I., …Huang, A. (2019). A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor. Cancer Cell, 36(1), 51-67.e7. https://doi.org/10.1016/j.ccell.2019.06.002

• Journal Article Type: Article
• Acceptance Date: Jun 3, 2019
• Online Publication Date: Jul 8, 2019
• Publication Date: Jul 8, 2019
• Deposit Date: Aug 7, 2019
• Publicly Available Date: Jul 9, 2020
• Journal: Cancer Cell
• Print ISSN: 1535-6108
• Electronic ISSN: 1878-3686
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Issue: 1
• Pages: 51-67.e7
• DOI: https://doi.org/10.1016/j.ccell.2019.06.002
• Keywords: Cell Biology; Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/2403904
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1535610819302934
• Additional Information: This article is maintained by: Elsevier; Article Title: A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor; Journal Title: Cancer Cell; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ccell.2019.06.002; Content Type: article; Copyright: © 2019 Elsevier Inc.