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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clinical presentation varies among patients with CIC-rearrangements.
• CIC::DUX4 fusions are linked to soft tissue tumors, while CIC::NUTM1 fusions affect the central nervous system.
• The molecular basis for these clinical differences is unclear due to limited tools.

Purpose of the Study:

• To develop and validate synthetic CIC fusion constructs for studying their distinct biological activities.
• To investigate the mechanistic differences between CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 fusions.
• To provide novel molecular tools for researching CIC-family fusions.

Main Methods:

• Generated patient-informed synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4.
• Performed structure-function studies to analyze fusion protein activity.
• Utilized genetic zebrafish models to validate the functional impact of these fusions.

Main Results:

• CIC::NUTM1 induced a unique transcriptional program, distinct from CIC::DUX4, due to its C-terminal domain.
• CIC::LEUTX demonstrated weak activation of CIC target genes via LEUTX transactivation sequences.
• ATXN1::DUX4 upregulated CIC target genes through the ATXN1 AXH domain.

Conclusions:

• The binding partner of CIC significantly influences the activity of the fusion oncoprotein.
• These synthetic tools offer insights into partner gene-specific biology of CIC-family fusions.
• This work provides a resource for studying rare cancers driven by CIC-family rearrangements.