First Generation Tools for the Modeling of Capicua (CIC) - Family Fusion Oncoprotein-Driven Cancers.

Clinical divergence between patients harboring -rearrangements is frequently observed. For example, the prototypical fusion associates with soft tissue tumors while fusions typically localize to the CNS (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 , , and and validated them in structure-function studies. 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 fusion binding partner may alter overall fusion oncoprotein activity. Thus, these first generation synthetic tools provide an unprecedented resource to study -family fusions beyond and allow for the dissection of this rare subgroup of cancers.