Abstract A050 DNMT3B DNA methyltransferase acts as a major player and therapeutic target in rhabdoid tumors
Bibliographic record
Abstract
Abstract Rhabdoid tumors (RTs) are highly aggressive pediatric malignancies which occur in kidney, soft-parts and brain, where they are named AT/RT. RTs are characterized by the inactivation of the SMARCB1 tumor suppressor gene encoding a core subunit of the chromatin remodeling SWI/SNF complex, which is the only recurrent genetic event, rendering this malignancy a prototype of epigenetically-driven cancers. Hence, targeting epigenetic modifyers by so-called « epidrugs » is an attractive hypothesis for treatment of RTs. Interestingly, several studies have pointed out the overexpression of de novo DNA methyl transferases, i.e. DNMT3A and DNMT3B, in RTs, but their role in RT oncogenesis remains to be defined. Of note, we noticed that DNMT3A and DNMT3B expression is induced by SMARCB1 loss in a composite tumor that harbors both SMARCB1 proficient and SMARCB1 deficient components, which methylation profiles strongly differ from each other. To investigate their actual role in RTs, we knocked-out DNMT3A or DNMT3B in the I2A inducible RT cell line allowing the re-expression of SMARCB1. We demonstrated that both DNMT3A and DNMT3B KO affected I2A cell viability, showing the RT vulnerability to those genes, but with a more important dependency to DNMT3B than to DNMT3A. DNMT3B loss largely impacted gene expression and DNA methylation, much more than DNMT3A loss. We further investigated the overlap between DNMT3A/DNMT3B and SMARCB1 functions at the transcriptional level. We found that 43% of the genes deregulated after SMARCB1 re-expression were also deregulated by DNMT3B loss and mostly in the same direction. Those commonly differentially regulated genes were involved in development and cell adhesion. In contrast, only 19% of the genes deregulated after SMARCB1 re-expression were deregulated after DNMT3A loss. In conclusion, DNMT3B KO recapitulates SMARCB1 re-expression effect on gene expression showing that DNMT3B and SMARCB1 play antagonistic roles in cell adhesion and developmental programs. We finally demonstrated that the use of nanaomycin A, a specific DNMT3B inhibitor, as strong cytotoxic effects on RT cell lines, confirming that targeting DNMT3B offers a true vulnerability for RT that opens promising perspectives for innovative treatment. Citation Format: Céline Chauvin, Mamy Andrianteranagna, Sandrina Turczynski, Joanna Cyrta, Arnault Tauziede-Espariat, Rachida Bouarich, Zhi-Yan Han, Julien Masliah-Planchon, Gaelle Pierron, Mylène Bohec, Sylvain Baulande, Sergio Roman-Roman, Olivier Delattre, Franck Bourdeaut. DNMT3B DNA methyltransferase acts as a major player and therapeutic target in rhabdoid tumors [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 A050.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 0.000 |
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 teacher head, 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".