PDTM-22. A C19MC-LIN28A-MYCN ONCOGENIC CIRCUIT DRIVEN BY HIJACKED SUPER-ENHANCERS IS A DISTINCT THERAPEUTIC VULNERABILITY IN ETMRS – A LETHAL BRAIN TUMOR

Autor:	Xiao-Nan Li, Jeremy N. Rich, Tannu Suwal, Irtisha Singh, Stephen C. Mack, Annie Huang, Charles Y. Lin, Patrick Sin-Chan, Iqra Mumal
Rok vydání:	2019
Předmět:	Cancer Research Programmed cell death Pediatric Tumors DNMT3A Gene Brain tumor Cancer Cell cycle Biology medicine.disease Neural stem cell Fusion gene Oncology medicine Cancer research Neurology (clinical) Enhancer
Zdroj:	Neuro Oncol
ISSN:	1523-5866 1522-8517
Popis:	Embryonal tumors with multi-layered rosettes (ETMR) are aggressive brain cancers with characteristic C19MC oncomiR amplification and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a potent C19MC-LIN28A-MYCN circuitry driven by multiple regulatory loops and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. C19MC and LIN28A targets respectively converge on critical cell cycle tumor suppressors and neo-embryonic DNMT3A/B isoforms. We identify a MYCN driven, core transcriptional network, conserved in early neural stem cells, that is potently abrogated by treatment with bromodomain inhibitor JQ1, leading to ETMR cell death. Our collective data suggest C19MC oncomiRs drive a malignant primitive cell state in ETMRs via entrapment of an early neural lineage network, which represents a critical therapeutic vulnerability for this recalcitrant disease.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34470e8a399501042e4bea1f412958ab https://doi.org/10.1093/neuonc/noz175.798 Zobrazit plný text záznamu