Abstract 2718: Investigating the interaction of NF1 with the Polycomb Repressive Complex 2

Abstract Neurofibromin 1 (NF1) is a tumor suppressor gene frequently mutated in myeloid leukemias. The encoded neurofibromin protein negatively regulates the RAS pathway in the cytosol. Inactivating mutations in NF1 lead to hyperactive RAS signaling, phenocopying activating mutations in RAS itself. This aberrant signaling drives downstream activation of pathways such as MAPK and PI3K/Akt/mTOR. Despite the prevalence of NF1-mutated leukemia, effective therapies remain elusive, highlighting the need for a deeper understanding of NF1-mediated leukemogenesis. To identify key dysregulated genes in NF1-driven leukemogenesis, we performed bulk RNA sequencing on hematopoietic stem cells from Nf1 knockout mice exhibiting myelodysplastic syndrome. Gene set enrichment analysis revealed significant dysregulation of pathways involved in histone methylation and RNA modification. Etv4, Id2, and Bcl6 were among the top upregulated genes, although their dysregulation is likely secondary to RAS activation. To uncover novel, non-canonical targets of NF1, we identified Phf19 as a dysregulated gene not directly regulated by RAS. PHD finger protein 19 (PHF19) is a component of the Polycomb Repressive Complex 2 (PRC2), a complex that mediates histone H3 lysine 27 trimethylation (H3K27me3) through the catalytic activity of EZH2. This finding is particularly intriguing as previous studies have suggested nuclear localization of neurofibromin, but its function in the nucleus has remained unclear. To explore the potential nuclear role of neurofibromin, we employed TurboID proximity labeling to identify its interaction partners in both the nucleus and cytoplasm. We found that neurofibromin interacts with the core PRC2 components EZH2 and SUZ12 in the nucleus, a finding confirmed by co-immunoprecipitation. Ongoing studies aim to elucidate the functional consequences of Phf19 upregulation and the impact of the neurofibromin-PRC2 interaction on apoptosis, cell cycle progression, and proliferation in Nf1 knockout mouse model. Citation Format: Asra Noor, Peng Zhang, Pinpin Sui, Feng-Chun Yang. Investigating the interaction of NF1 with the Polycomb Repressive Complex 2 [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 2718.