Functional genomics screen reveals SFPQ as a regulator of cell state in IDH-mutant glioma

Abstract

Gliomas are the most common central nervous system tumors in adults and are characterized by profound intra-tumoral heterogeneity. Their classification is based on histopathological features, molecular genetic alterations, and tumor aggressiveness. Among these, isocitrate dehydrogenase (IDH) mutations are frequently observed and are now established as key markers in CNS tumor classification. Although mutant IDH inhibitors are the center of therapeutic strategies, the identification of epigenetic vulnerabilities may reveal additional and complementary therapeutic intervention points. To systematically uncover epigenetic regulators essential for IDH-mutant glioma viability, we performed a pooled CRISPR/Cas9-based epigenetic knockout screen in patient-derived IDH-mutant gliomasphere models. This screen identified SFPQ (splicing factor proline- and glutamine-rich) as one of the most significantly depleted genes, suggesting its critical role in tumor cell survival in this context. To investigate the functional consequences of SFPQ loss, we performed bulk RNA sequencing following SFPQ knockout. Transcriptomic profiling revealed downregulation of synaptic organization, proneuronal, and neuronal gene programs, accompanied by a shift toward a mesenchymal-like state characterized by activation of TNFα–NF-κB and interferon signaling pathways. In vivo studies to further validate these findings are currently ongoing. Collectively, these findings identify SFPQ as a previously unrecognized regulator of lineage state maintenance in IDH-mutant glioma and nominate SFPQ as a potential epigenetic vulnerability with therapeutic relevance. Citation Format: Ebru Yilmaz, Aybala Samancioglu, Alexander Jucht, Sedef Sarac-Yalcinkaya, Mario L. Suva, Tugba Bagci-Onder. Functional genomics screen reveals SFPQ as a regulator of cell state in IDH-mutant glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A034.