Abstract 3657: Defining the role of the RNA-binding protein MSI2 in neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood with a 5-year survival rate approaching 50% in high-risk patients and like other pediatric cancers, lacks many targetable mutations. Thus, novel therapeutic approaches are needed. Previous research has shown that the RNA-binding protein (RBP), LIN28B, enhances MYCN expression and induces NB formation. Additionally, we previously demonstrated that LIN28B-RAN-AURKA signaling drives NB oncogenesis. These results highlight the role of RBPs in modulating NB tumorigenesis. The Musashi family includes RBPs that have been previously shown to be associated with worse prognosis in adult malignancies, including colon cancer and pancreatic cancer, among others. Thus, we speculated that the Musashi family might influence aggressive phenotypes in pediatric tumors, such as neuroblastoma. MSI2 is robustly expressed in neuroblastoma tumors, and, indeed, increased levels of Musashi-2 ( MSI2 ) correlate with worse NB prognosis. In order to begin to elucidate its role in NB tumorigenesis, we knocked-down MSI2 in human NB cell lines using multiple independent short hairpin RNAs (shRNA) and small interfering RNAs (siRNA) and examined the impact on proliferation, survival, and downstream target genes relative to scrambled control RNA-treated cells. From these experiments, we observed decreased colony formation in clonogenic assays, increased apoptosis and decreased proliferation. To gain an initial understanding of the downstream targets that MSI2 influences, we performed Nanostring analysis in 2 human NB cell lines, Kelly and SK-N-DZ and found that knocking down MSI2 led to a downregulation of many cancer-related genes including IDH2 and other metabolic targets. IDH2 is a mitochondrial enzyme and its mutant is known to be involved in gliomagenesis. Changes in IDH2 expression have also been linked to epigenetic alterations. Finally, wild-type IDH2is upregulated in lung cancer and contributes to tumor growth. Therefore, we are currently examining the functional relationship between MSI2 and IDH2 in NB. Citation Format: Adeiye Pilgrim, Selma Cuya, Dongdong Chen, Robert Schnepp. Defining the role of the RNA-binding protein MSI2 in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3657.