Abstract B024: <i>SRF</i> fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors

Abstract SRF fusion genes drive the pathogenesis of muscle-related soft tissue tumors, including subsets of perivascular tumors, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. SRF encodes Serum Response Factor, a well-characterized transcription factor that regulates muscle development. We characterized four fusion genes: SRF::RELA, SRF::FOXO1, SRF::ICA1L, and SRF::PDGFRB. All localized to the nucleus and dimerized through the SRF MADS box. SRF::RELA, SRF::FOXO1, and SRF::ICA1L acted as constitutively active transcription factors independent of canonical cofactors, binding SRF target promoters and driving transcription via the partner transactivation domain (TAD). A cryptic TAD was uncovered in ICA1L. These fusions promoted mesenchymal cell growth and upregulated muscle-related genes in mesenchymal stem cells, recapitulating transcriptional signatures of human tumors. In contrast, SRF::PDGFRB acted through its kinase domain, was imatinib-sensitive, activated STAT1 and stimulated inflammation genes, consistent with its tumor phenotype. SRF fusions thus define a novel family of oncogenes in human myoid soft tissue tumors. Citation Format: Constance Pirson, Ariane Sablon, Axelle Loriot, Pierre Autin, A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin. SRF fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors [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 B024.