Abstract B17: A <i>C19MC</i>-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs—a lethal brain tumor
Bibliographic record
Abstract
Abstract Embryonal tumors with multilayered rosettes (ETMRs) are distinctly challenging brain tumors of infants and very young children, with characteristic rapid progression and only 10-20% overall survival. ETMRs have characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Since the discovery of C19MC, an embryonic stem cell-enriched, primate specific miRNA cluster, as a disease marker of ETMR, there has been limited progress in biologic and therapeutic understanding of this disease. In prior studies we demonstrated single C19MC oncomiRs promotes oncogenesis and inhibit neural differentiation, yet the specific mechanisms of C19MC remains unclear. Here we show expression of 5-C19MC oncomiRs cooperatively inhibits multiple cell cycle checkpoint tumor suppressors to drive cellular proliferation. We further show that C19MC oncomiRs activate a potent oncogenic circuit by upregulating MYCN and LIN28A via downregulation of RNA binding protein, Tristetraprolin. Using RNA-IP analyses, we uncovered epigenetic regulators as major targets of LIN28A and showed that LIN28A directly regulates expression of embryonic-neural DNMT3A2 and DNMT3B6 isoforms. Deep epigenetic mapping on primary tumors revealed high DNA-DNA interactions and enhancer hijacking focused on MYCN. We also discovered tumors with TTYH1-C19MC gene fusions harbored a novel hybrid super-enhancer. Lastly, super-enhancer analysis revealed MYCN/MAZ as major transcriptional regulators and that treatment with a potent MYCN and bromodomain inhibitor JQ-1 inhibited proliferation of primary cells. Collectively, our data reveal that tumor-specific genomic and epigenomic alterations of C19MC entrap and drive multiple feed-forward loops to fuel a potent C19MC-LIN28A-MYCN oncogenic circuit, that can be powerfully abrogated by bromodomain inhibitors. Our findings underscore C19MC as a critical oncogene in ETMRs and provide critical therapeutic insights and a framework for developing high-fidelity models for this orphan disease. Citation Format: Iqra Mumal, Patrick Sin-Chan, Tannu Suwal, Irtisha Singh, Xiao-Nan Li, Charles Lin, Stephen Mack, Jeremy Rich, Annie Huang. A C19MC-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs—a lethal brain tumor [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B17.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".