A NOVEL GEMM TO ELUCIDATE THE ROLE OF CHAF1A IN NEUROBLASTOMA DEVELOPMENT

This proposal focuses on the fundamental understanding on how the CHAF1A oncogene drives molecular mechanisms, cellular signaling, and metabolic processes in the oncogenesis of neuroblastoma (NB). NB is an aggressive pediatric cancer, which accounts for 15% of pediatric cancer mortalities. High-risk NB is thought to arise from a small number of recurrent genetic alterations that block the ability of neural crest cells (NCCs) to differentiate. To assess the molecular mechanisms governing NC differentiation, our laboratory has established a definitive role of the epigenetic regulator CHAF1A in blocking NC differentiation and driving NB oncogenesis. In this proposal, we will determine the impact of CHAF1A on NB initiation and progression. To accomplish this goal, we propose to develop a novel CHAF1A-driven genetically-engineered mouse model (GEMM) of NB and test the impact of CHAF1A on NB incidence, histology and metastasis, and the tumor immune microenvironment (TIME). We hypothesize that CHAF1A will increase de novo incidence of NB, reduce mouse survival, and promote a suppressive TIME. By developing a novel GEMM of NB and employing innovative technology (including ATAC-seq, lipidomics, and scRNA-seq), we will: 1- elucidate the role of CHAF1A in NB tumor initiation and progression; and 2- determine the impact of CHAF1A on MYCN-induced oncogenesis. These findings will provide a novel view on the molecular mechanisms driving NB initiation, and will have high clinical implications, informing future differentiation-based interventions for high-risk NBs. Project Number: 1R03NS140939-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Eveline Barbieri | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $160,500 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 BTC-F (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301336