Publication: A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.
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Date
2019
Authors
Sin-Chan, Patrick
Mumal, Iqra
Suwal, Tannu
Ho, Ben
Fan, Xiaolian
Singh, Irtisha
Du, Yuchen
Lu, Mei
Patel, Neilket
Torchia, Jonathon
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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.
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MeSH Terms
Biomarkers, Tumor
Brain Neoplasms
Cell Cycle
Cell Transformation, Neoplastic
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
Models, Biological
Multigene Family
N-Myc Proto-Oncogene Protein
Neoplasms, Germ Cell and Embryonal
Oncogenes
RNA-Binding Proteins
Brain Neoplasms
Cell Cycle
Cell Transformation, Neoplastic
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
Models, Biological
Multigene Family
N-Myc Proto-Oncogene Protein
Neoplasms, Germ Cell and Embryonal
Oncogenes
RNA-Binding Proteins
DeCS Terms
CIE Terms
Keywords
C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics