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.

• Authors: Patrick Sin-Chan, Iqra Mumal, Tannu Suwal, Ben Ho, Xiaolian Fan, Irtisha Singh, Yuchen Du, Mei Lu, Neilket Patel, Jonathon Torchia, Dean Popovski, Maryam Fouladi, Paul Guilhamon, Jordan R Hansford, Sarah Leary, Lindsey M Hoffman, Jean M Mulcahy Levy, Alvaro Lassaletta, Palma Solano-Paez, Eloy Rivas, Alyssa Reddy, G Yancey Gillespie, Nalin Gupta, Timothy E Van Meter, Hideo Nakamura, Tai-Tong Wong, Young-Shin Ra, Seung-Ki Kim, Luca Massimi, Richard G Grundy, Jason Fangusaro, Donna Johnston, Jennifer Chan, Lucie Lafay-Cousin, Eugene I Hwang, Yin Wang, Daniel Catchpoole, Jean Michaud, Benjamin Ellezam, Ramya Ramanujachar, Holly Lindsay, Michael D Taylor, Cynthia E Hawkins, Eric Bouffet, Nada Jabado, Sheila K Singh, Claudia L Kleinman, Dalia Barsyte-Lovejoy, Xiao-Nan Li, Peter B Dirks, Charles Y Lin, Stephen C Mack, Jeremy N Rich, Annie Huang
• Journal: Cancer cell (Cancer Cell) Vol. 36 Issue 1 Pg. 51-67.e7 (07 08 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31287992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Lin28A protein, human
• MicroRNAs
• N-Myc Proto-Oncogene Protein
• RNA-Binding Proteins

Topics

• Biomarkers, Tumor
• Brain Neoplasms (diagnosis, etiology, therapy)
• Cell Cycle (genetics)
• Cell Transformation, Neoplastic (drug effects, genetics)
• Chromosomes, Human, Pair 19
• Chromosomes, Human, Pair 2
• DNA Copy Number Variations
• Enhancer Elements, Genetic
• Epigenesis, Genetic
• Gene Expression Regulation
• Gene Regulatory Networks
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• MicroRNAs (genetics)
• Models, Biological
• Multigene Family
• N-Myc Proto-Oncogene Protein (genetics)
• Neoplasms, Germ Cell and Embryonal (diagnosis, etiology, therapy)
• Oncogenes
• RNA-Binding Proteins (genetics)