Abstract B010: Biological consequences of neural signatures in fusion-positive rhabdomyosarcoma
Bibliographic record
Abstract
Abstract Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer with features of arrested skeletal muscle development. PAX3::FOXO1 is the most common and lethal fusion-oncogene of this disease and arises from a translocation between the DNA binding domains of PAX3 with the transactivation domain of FOXO1. This chimeric transcription factor is required for tumor initiation and has pioneering activity allowing it the unique potential to bind to inaccessible chromatin to make regions amenable to transcription. Despite PAX3::FOXO1’s identification over thirty years ago, and well-characterized importance in this disease, we still lack targeted therapies that significantly improve patient outcomes. Furthermore, it has been technically challenging to investigate the initial in vivo activities of PAX3::FOXO1 and how it could establish a tumorigenic cell fate. Here, we established a PAX3::FOXO1 mRNA zebrafish injection model and quantitative spike-in ChIP-seq analytical pipeline to evaluate how PAX3::FOXO1 initially interfaces with chromatin in a developmental context. In our approach, we inject human PAX3::FOXO1 mRNA into zebrafish embryos and observe broad protein expression during early development, peaking at six hours-post fertilization during gastrulation. We then characterized PAX3::FOXO1 activity with 2D chromatin-sequencing and transcriptional profiling. Transcriptionally, we observe the upregulation and enrichment for rhabdomyosarcoma-associated genes and pathways. Further, we find that PAX3::FOXO1 has nucleosomal binding. Using 2D chromatin sequencing, we observe that PAX3::FOXO1 localizes within inaccessible chromatin through partial homeobox motif recognition, consistent with pioneering activity. In contrast, PAX3::FOXO1 binding through its composite motif modifies chromatin accessibility and re-distributes H3K27ac to activate neural transcriptional programs. This includes neural transcriptional signatures found in PAX3::FOXO1 patient tumors, and that are induced in patient-derived xenografts in response to chemotherapy. Our long-term goal is to do comparative analyses across our mRNA injection and zebrafish rhabdomyosarcoma tumor models and patient data to identify conserved PAX3::FOXO1 mechanisms and targets across stages of tumorigenesis. This injection model is versatile, allowing us to functionally evaluate cooperation between PAX3::FOXO1 and other factors of interest. Altogether, we can provide valuable insight into chromatin regulation, which may be applicable across other cancers and development. Citation Format: Jack Kucinski, Alexi Tallan, Cenny Taslim, Meng Weng, Matthew Cannon, Katherine Silvius, Benjamin Z. Stanton, Genevieve C. Kendall. Biological consequences of neural signatures in fusion-positive rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B010.
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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".