@article{8ab1cd9d98e5460397dfe1d4f4a17478,
title = "A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor",
abstract = "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.",
keywords = "Biomarkers, Tumor, Brain Neoplasms, C19MC, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, ETMR, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, LIN28A, MYCN, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Biomarkers, Tumor, Brain Neoplasms, C19MC, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, ETMR, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, LIN28A, MYCN, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics",
author = "Patrick Sin-Chan and Iqra Mumal and Tannu Suwal and Ben Ho and Xiaolian Fan and Irtisha Singh and Yuchen Du and Mei Lu and Neilket Patel and Jonathon Torchia and Dean Popovski and Maryam Fouladi and Paul Guilhamon and Hansford, {Jordan R.} and Sarah Leary and Hoffman, {Lindsey M.} and {Mulcahy Levy}, {Jean M.} and Alvaro Lassaletta and Palma Solano-Paez and Eloy Rivas and Alyssa Reddy and Gillespie, {G. Yancey} and Nalin Gupta and {Van Meter}, {Timothy E.} and Hideo Nakamura and Tai-Tong Wong and Young-Shin Ra and Seung-Ki Kim and Luca Massimi and Grundy, {Richard G.} and Jason Fangusaro and Donna Johnston and Jennifer Chan and Lucie Lafay-Cousin and Hwang, {Eugene I.} and Yin Wang and Daniel Catchpoole and Jean Michaud and Benjamin Ellezam and Ramya Ramanujachar and Holly Lindsay and Taylor, {Michael D.} and Hawkins, {Cynthia E.} and Eric Bouffet and Nada Jabado and Singh, {Sheila K.} and Kleinman, {Claudia L.} and Dalia Barsyte-Lovejoy and Xiao-Nan Li and Dirks, {Peter B.} and Lin, {Charles Y.} and Mack, {Stephen C.} and Rich, {Jeremy N.} and Annie Huang",
year = "2019",
doi = "10.1016/j.ccell.2019.06.002",
language = "English",
volume = "36",
pages = "51--67.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
}
