Abstract IA003: Intersecting Developmental and Oncogenic Networks in ZFTA Fusion-Driven Brain Cancer

Abstract Brain tumors are the leading cause of cancer-related death in children. Ependymoma (EPN) is a devastating pediatric brain tumor with only ∼50% survival, currently treated with non-targeted approaches such as surgery and irradiation. Over 70% of EPNs arising in the brain cortex are driven by a gene fusion between ZFTA and RELA (ZR). ZR is a potent oncogenic driver capable of initiating brain tumors when expressed alone in mouse or human neural stem/progenitor cells. Despite its strong transforming capacity, the molecular mechanisms and cell types that give rise to EPN remain unclear. We hypothesized that the ZR fusion oncoprotein functions as an oncogenic transcription factor (TF), engaging distinct genomic loci accessible during embryonic brain development. Our findings demonstrate that ZR binds specific Plag/l TF motifs that are accessible in radial glial and cycling progenitor cell sduring mouse and human neocortical development. The oncogenic activity of ZR depends on a key intrinsically disordered region (IDR) that promote biomolecular condensate formation, regulates gene transcription, and governs chromatin binding. Finally, lineage tracing of natively forming mouse ZR tumors reveals the emergence of dominant clones driven by ZR expression, which induce transcriptional plasticity through impaired neuronal and glial differentiation programs. Together, these findings uncover critical molecular and developmental mechanisms of ZR fusion oncoprotein, providing a foundation for future therapeutic strategies. Citation Format: Stephen C. Mack. Intersecting Developmental and Oncogenic Networks in ZFTA Fusion-Driven Brain Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA003.