Abstract A012 Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d
Bibliographic record
Abstract
Abstract METTL1 is an RNA methyltransferase which catalyzes N7-methylguanosine (m7G) methylation on various RNAs, particularly on tRNAs. METTL1 has been reported to be amplified and/or overexpressed and high expression correlates with poor patient prognosis in different types of adult cancers. Our ZERO Childhood Cancer Program focuses on identifying and validating potential new drug targets and developing novel therapies for clinical use. ZERO has sequenced the whole genome and transcriptome in over 500 high-risk pediatric tumors and found that METTL1 gene copy number and gene expression are significantly higher in a subset of high-grade glioma, neuroblastoma, diffuse midline glioma and fusion positive rhabdomyosarcoma. Analysis of the publicly available SEQC microarray dataset showed that high METTL1 expression correlates with poor outcomes in MYCN amplified neuroblastoma patients. We validated the functional roles of METTL1 gene amplification and overexpression in a few pediatric cancer cell line models using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Cas13d knockdown system, in dual lentiviral constructs. We found that knocking down METTL1 significantly decreased METTL1 amplified neuroblastoma and rhabdomyosarcoma cell viability and colony formation but not in METTL1 non-amplified neuroblastoma and rhabdomyosarcoma cells. Gene Set Enrichment Analysis from RNA sequencing data revealed that knocking down METTL1 resulted in a decrease in Myc target gene expression, and an increased in apoptosis, interferon alpha response and p53 pathway hallmarks. Western blot analysis confirmed that knocking down METTL1 led to a decrease in the MCL-1 antiapoptotic protein expression and an increase in the proapoptotic protein expression such as cleaved PARP and caspase 3. Taken together, our data demonstrate that METTL1 is a potential therapeutic target in METTL1 amplified pediatric cancers. Citation Format: Pei Y. Liu, Steven He, Chelsea Mayoh, Alice Salib, Antoine De Weck, Paul G. Ekert. Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d [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 A012.
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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) | 0.002 | 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".