Abstract B54: Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma
Bibliographic record
Abstract
Abstract Alveolar soft part sarcoma (ASPS) predominantly affects adolescents and young adults, with lower legs and buttocks as frequent primary sites. ASPS is characterized by alveolar structure of tumor cells, abundant vascularization, and frequent hematogenous metastasis. As for gene abnormality, the ASPSCR1-TFE3 (AT3) fusion is invariably observed in all ASPS cases with low genetic mutational burdens. To understand the functional roles of AT3 in ASPS development, we have generated an ex vivo mouse model for ASPS that well recapitulates its phenotypes. TFE3 belongs to the MiT/TFE (TFE3/TFEB/TFEC/MITF) gene family encoding bHLH/leucine zipper transcription factors, all of which share common DNA-binding domains and consensus DNA-binding motifs. Mutations or overexpression of MiT/TFE family genes trigger human malignancies including ASPS, renal cell carcinoma (RCC), and malignant melanoma (MM). To address whether AT3 possesses a specific potency to induce ASPS, we have generated artificial chimeras between ASPSCR1 and MiT/TFE family genes and have revealed that only TFE3 and TFEB could induce ASPS in vivo whereas the others could not. To get insights into the role of AT3 in enhancer reprogramming that affects tumor phenotypes, we investigated the epigenetic landscape of ASPS. ChIP-seq analyses of human and mouse ASPS showed frequent overlapping of AT3 DNA-binding with histone H3K27ac and H3K4me3 at target loci, indicating that AT3 frequently binds to active enhancers. Among them, canonical MiT/TFE target genes involved in the autophagy, lysosome/endosome and vesicle/protein transport, and mTOR signaling pathways were significantly enriched. Analysis of dataset from GEO revealed that these loci were common targets of MiT/TFE transcription factors activated in human ASPS, RCC, and MM. To identify the AT3-specific and/or AT3-dependent enhancer reprograming mechanism, we focused on super-enhancers (SEs) that determine the cell identity and characteristic phenotypes of ASPS, and examined its modification by AT3. Frequent association of SEs with genes for vasculogenesis and apoptosis were observed in ASPS but not in MM, and AT3 depletion in ASPS resulted in disappearance of these SEs, suggesting that AT3 contributes to chromatin remodeling to promote vasculogenesis required for its alveolar structure and growth expansion. Taken together, our study provides novel aspects on common oncogenic pathways regulated by MiT/TFE family tumor in ASPS, RCC, and MM as well as AT3-specific regulatory mechanism in ASPS, which will offer potential therapeutic targets and biomarkers. Citation Format: Miwa Tanaka, Takuro Nakamura. Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma [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 B54.
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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".