Abstract A015: Lowering barriers to studying <i>CIC</i> - and <i>ATXN1</i> -rearranged cancers

Abstract The extreme rarity of certain fusion-oncogene-driven cancers limits dedicated mechanistic study and the potential development of new therapies. Beyond simple expression constructs, only a select few fusion-driven cancers have had synthetic tools engineered which enable complex and thorough biological dissection of these driver events. In this work, we focus on facilitating access to research focused on fusion genes involving capicua (CIC) and ataxin 1 (ATXN1). While prior work from our group and others has led to advances in modeling CIC::DUX4 sarcoma, no tools have existed to study fusions involving other 3’ partners including CIC::NUTM1 and CIC::LEUTX, which have different clinical characteristics compared to CIC::DUX4. We use the first models of CIC::NUTM1 and CIC::LEUTX to evaluate the gene programs they drive and the functional domains they rely on to function. We characterize a novel region within the NUTM1 fragment of CIC::NUTM1, which enables expression of hundreds of genes not strongly induced by CIC::DUX4 in 293T cells. This molecular divergence has potential implications for the identification of the CIC::NUTM1 cell of origin. We also find two LEUTX transactivating domains as key for CIC::LEUTX-mediated transcriptional activation of a CIC target gene, potentially highlighting a therapeutic vulnerability. Finally, we build and characterize the first model of ATXN1 (a known CIC interactor) containing fusions, including ATXN1::DUX4 tumors, which constitute a rare but interesting class of fusions that potentially co-opt native CIC interactions to drive tumorigenesis. Beyond transcriptional events, we have engineered tools to study CIC::DUX4 at the cellular level. Specifically, we developed tools for microscopic visualization (mStayGold tag) and proximity labelling (TurboID tag) of the CIC::DUX4 fusion oncoprotein. These tools will facilitate our understanding of CIC::DUX4-mediated cellular interactions and function, improving our understanding of it to a level comparable to that of the more well studied EWS::FLI or PAX::FOXO fusions. Collectively, we have developed a suite of ready-made tools and model systems to scientifically and clinically advance the study of CIC- and ATXN1-rearranged cancers. A major goal of this project is to provide the research community with CIC and ATXN1 fusion tools and resources to advance therapies and improve outcomes for these devastating and understudied diseases. Citation Format: Cuyler Luck, Ross A. Okimoto. Lowering barriers to studying CIC- and ATXN1-rearranged cancers [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 A015.