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

Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): 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 RivasSummaryEmbryonal 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research