Abstract B37: Menin and EWS/FLI1 activate serine biosynthesis via ATF4 in Ewing sarcoma
Bibliographic record
Abstract
Abstract Ewing sarcoma (ES) is an aggressive bone and soft-tissue tumor, most commonly driven by the EWS/FLI1 fusion oncogene. Previous work has revealed that the scaffolding protein menin functions to promote ES tumorgenicity. Additionally, our recent studies revealed a previously undescribed role for menin in the activation of the serine biosynthetic pathway (SSP), a critical metabolic pathway that is aberrantly activated in many human cancers. The transcription factor ATF4 has been identified in other tumor types as a master transcriptional regulator of the SSP. Furthermore, regulation of the SSP by EWS/FLI1 has been described, although the mechanism of this regulation remains unknown. The biologic functions of menin are largely determined by its protein-binding partners, the best characterized of which is MLL in epigenetic trithorax complexes. In the current study, we are investigating the mechanistic link between menin, EWS/FLI1, and SSP hyperactivation to test the hypothesis that, in the context of ES, these transcriptional regulators cooperate to promote metabolic reprogramming via ATF4. Through gain- and loss-of-function studies, our results show that ATF4 regulates the SSP in ES cells, and that loss of ATF4 impairs ES cell proliferation. Additionally, both pharmacologic inhibition with the menin:MLL interaction inhibitor, MI-503, and doxycycline-inducible shRNA knockdown of menin lead to loss of ATF4, coincident with loss of SSP expression. Knockdown of EWS/FLI1 similarly results in loss of both ATF4 and SSP expression. Interrogation of publicly available ChIP-seq data further shows enrichment for EWS/FLI1 binding at the ATF4 gene promoter that is lost with EWS/FLI1 knockdown, and ChIP-qPCR shows menin binding at the ATF4 gene promoter in association with H3K4me3 enrichment. ChIP-qPCR also shows enrichment of ATF4 binding at SSP gene promoters, which is diminished upon menin inhibition with MI-503. Preliminary studies suggest that ATF4 overexpression may rescue the effects of menin loss of function on the SSP. Together these findings support the hypothesis that menin hijacks the SSP via aberrant activation of ATF4, and that this depends on cooperation with EWS/FLI1. Ongoing studies are assessing whether this is mediated by trithorax-dependent or -independent functions of menin. Citation Format: Jennifer A. Jiménez, Ramon Ocadiz Ruiz, April Apfelbaum, Abhijay Kumar, Samuel Kerk, Jolanta Grembecka, Costas A. Lyssiotis, Elizabeth R. Lawlor. Menin and EWS/FLI1 activate serine biosynthesis via ATF4 in Ewing 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 B37.
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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 | 0.000 |
| 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".