Abstract 2613: The role of the RNA methyltransferase RNAMT1 as a tumorigenic driver and therapeutic target in neuroblastoma

Abstract Neuroblastoma is the most common extracranial solid tumor in children worldwide. We have found that high expression of the RNAMT1 gene in tumor tissues is associated with poor prognosis in both MYCN-amplified [Overall survival (OS): p = 0.0409 and event-free survival (EFS): p = 0.0061] and MYCN non-amplified neuroblastoma patients (OS: p < 0.0001 and EFS: p < 0.0001). Multivariable Cox regression analysis for neuroblastoma patient prognosis of RNAMT1 gene expression [OS: hazard ratio (HR) = 1.92, p = 0.003 and EFS: HR = 1.72, p = 0.0001] is independent from current prognostic markers: MYCN amplification (OS: HR = 3.39, p = 5.1E-8 and EFS: HR = 1.77, p = 0.0001), age older than 18 months (OS: HR = 2.73, p = 2.9E-5 and EFS: HR = 1.59, p = 0.01), and International Neuroblastoma Staging System stages 3&4 (OS: HR = 5.68, p = 5.00E-6 and EFS: HR = 3.00, p = 6.83E-8). Doxycycline (DOX)-inducible RNAMT1 knockdown in MYCN-amplified and MYCN non-amplified neuroblastoma cells decreased cell viability and colony formation capability, and induced apoptosis in vitro. DOX-inducible RNAMT1 knockdown delayed tumor growth and improved survival in mice bearing SK-N-BE(2)-C shRNA1 (OS: p = 0.0034) and SK-N-AS shRNA2 (OS: p < 0.0001). RNAMT1 regulates protein translation based on previous literatures, we demonstrated that RNAMT1 did not affect global mRNA translation alteration via puromycin incorporation assay and slightly affected polysome profile. The subset of mRNA transcripts after RNAMT1 knockdown and RNAMT1 inhibitor treatment will be analyzed with translating ribosome affinity purification sequencing (TRAP-Seq). RNAMT1 inhibitor was discovered by AlphaScreen of 2952 small molecule compounds provided by National Cancer Institute (NCI). Unravelling the molecular mechanisms of RNAMT1 in neuroblastoma tumorigenesis and mechanism of actions of RNAMT1 inhibitor, may provide novel insights to develop a more effective treatment for neuroblastoma patients. Citation Format: Kian Chung Chok, Kenny Ip, Jing Wu, Satyanarayana Gadde, Sujanna Mondal, Justin Wong, Belamy Cheung, Tao Liu. The role of the RNA methyltransferase RNAMT1 as a tumorigenic driver and therapeutic target in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2613.