Modeling of Capicua Family Fusion Oncoprotein-Driven Cancers Reveals Gene-Specific Functionality.

Clinical divergence between patients harboring CIC-rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft tissue tumors while CIC::NUTM1 fusions typically localize to the central nervous system (brain/spinal cord). The basis for these differences is poorly understood due to a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies and in genetic zebrafish models. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 due to a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity. Implications: These first-generation synthetic tools illuminate partner gene-specific mechanistic biology while providing an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.