Abstract 2608: The super enhancer-driven long noncoding RNA lncNB promotes neuroblastoma tumorigenesis by interacting with MSI2 protein and is targetable by small molecule compounds

Abstract Background: While MYCN-amplified neuroblastoma has been the focus of neuroblastoma research in the past three decades, most human neuroblastomas do not harbour MYCN oncogene amplification, and their tumorigenic factors are unknown. Long non-coding RNAs (lncRNAs) regulate tumorigenesis by modulating the expression of molecular targets, however, there is limited literature on therapeutic targeting of lncRNAs with small molecule compounds. Aims: To determine the oncogenic mechanism though which the lncRNA lncNB promotes neuroblastoma cell proliferation, survival and tumour progression; and to identify a small molecule compound that inhibits the interaction between lncNB and its binding protein MSI2 as an effective anticancer strategy. Methods and results: Kaplan Meier analysis showed that high levels of lncNB expression in neuroblastoma tissues correlated with poor prognosis in 476 patients. We identified lncNB as the lncRNA most over-expressed in MYCN non-amplified, compared with MYCN-amplified, neuroblastoma cell lines. lncNB expression was controlled by super-enhancers, and lncNB RNA bound to MSI2 protein. RNA immunoprecipitation and sequencing identified BMX mRNA as the transcript most significantly disrupted from binding to MSI2 protein, after lncNB knockdown. lncNB or MSI2 knockdown reduced, while their over-expression enhanced, BMX mRNA stability and expression, ERK protein phosphorylation and MYCN non-amplified neuroblastoma cell proliferation. lncNB knockdown significantly suppressed neuroblastoma progression in mice. AlphaScreen of a compound library identified NSC617570 as an efficient inhibitor of lncNB RNA and MSI2 protein interaction, and NSC617570 reduced BMX expression, ERK protein phosphorylation, neuroblastoma cell proliferation in vitro and tumor progression in mice. Conclusions: Our study demonstrates that lncNB RNA interacts with MSI2 protein to induce neuroblastoma tumorigenesis, and that targeting lncNB and MSI2 interaction with small molecule compounds is an effective anticancer strategy. Citation Format: Sujanna Mondal, Pei Y. Liu, Janith Seneviratne, Antoine De Weck, Pooja Venkat, Chelsea Mayoh, Jing Wu, Jesper Maag, Jingwei Chen, Matthew Wong, Nenad Bartonicek, Poh Khoo, Lei Jin, Louise E. Ludlow, David S. Ziegler, Toby Trahair, Pieter Mestdagh, Belamy B. Cheung, Jinyan Li, Marcel E. Dinger, Ian Street, Xu D. Zhang, Glenn M. Marshall, Tao Liu. The super enhancer-driven long noncoding RNA lncNB promotes neuroblastoma tumorigenesis by interacting with MSI2 protein and is targetable by small molecule compounds [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 2608.