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A C19MC-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs: A lethal brain tumor

AuthorsSin-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.; Levy, Jean M. Mulcahy; Lassaletta, Alvaro; Solano-Paez, Palma; Rivas Infante, 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
KeywordsBrain tumor
Issue Date2019
CitationCancer Cell 36(1): 51-67.e7 (2019)
AbstractEmbryonal 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.
Publisher version (URL)https://doi.org/10.1016/j.ccell.2019.06.002
Identifiersdoi: 10.1016/j.ccell.2019.06.002
issn: 1535-6108
e-issn: 1878-3686
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