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

Cancer Cell. 2019 Jul 8;36(1):51-67.e7. doi: 10.1016/j.ccell.2019.06.002.

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.

Keywords: C19MC; ETMR; LIN28A; MYCN; brain tumor; cell-cycle; epigenetics; microRNA; super-enhancer; therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / etiology*
  • Brain Neoplasms / therapy
  • Cell Cycle / genetics
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / 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
  • Neoplasms, Germ Cell and Embryonal / etiology*
  • Neoplasms, Germ Cell and Embryonal / therapy
  • Oncogenes
  • RNA-Binding Proteins / genetics*

Substances

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

Grants and funding