Abstract 4696: Oncogenic transcriptional rewiring in micronuclei

Abstract Chromosomal instability (CIN) is a well-known feature of aggressive tumors, yet the distinct oncogenic mechanisms associated with CIN remain an area of active discovery. We previously demonstrated that in addition to driving karyotypic heterogeneity, chromosomal localization into micronuclei (MN)—the extranuclear bodies formed from missegregated chromosomes— causes epigenetic dysregulation. Moreover, we and others had previously demonstrated that micronuclei were largely silenced. Here we took a multimodal approach to examine the transcriptional behavior of micronuclei, using imaging-based approaches as well as purification of nascent RNA from micronuclei. We show that despite global dampening, micronuclei are transcriptionally active. Across epithelial and cancer cell models, micronuclei display robust nascent RNA synthesis. GSEA of differentially expressed micronuclear genes reveals an enrichment of MYC programs as well as preferential transcription of short genes with fewer introns. This is consistent with constrained RNA processing within the micronuclear environment. Overexpression of a panel of transcription factors reveals that MYC upregulates micronuclear transcription. A chromosome-specific missegregation system confirms that these transcriptional effects occur on the missegregated chromosome itself, linking mitotic errors to locus-directed transcriptional change. Analyses of TCGA and SPECTRUM ovarian cancer datasets connect regions of copy number alteration with micronuclear transcriptional signatures, underscoring clinical relevance. Together, these findings establish a direct and novel relationship between chromosomal missegregation and oncogenic transcription. Chromosomal localization to micronuclei endows cancer cells with locus-specific transcriptional programs and reveals new oncogenic mechanisms in CIN-high disease. Citation Format: Duaa Hassan Al-Rawi, Danguole Norkunaite, Kaden Southard, Mercedes Duran, Xuelan Chen, Andrew William McPherson, Scott W. Lowe, Sohrab Shah, Samuel F. Bakhoum. Oncogenic transcriptional rewiring in micronuclei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4696.