Chromosomal translocations can generate oncofusion proteins that drive tumorigenesis. These oncofusions often combine transcription factor DNA binding domains to intrinsically disordered regions (IDRs) from diverse partner proteins to create potent cancer drivers in several pediatric and adult tumors. However, the molecular principles that enable these fusion proteins to hyperactivate transcription remain poorly understood. Recent work in the Sabari lab has revealed that many oncofusion IDRs share a distinct molecular signature defined by enrichment of certain amino acids, a pattern that is necessary and sufficient to confer aberrant transcriptional activation when tethered to chromatin. Despite this insight, the field lacks a mechanistic framework for understanding how dynamic, multivalent interactions mediated by IDRs generate functional specificity, and this gap has limited efforts to identify therapeutic vulnerabilities. This ASPIRE award supports a project that will define the biochemical and biophysical rules underlying oncofusion IDR function, using ASPL-TFE3 and NUP98-HOXA9 as exemplar fusions with broad relevance across oncofusion-driven malignancies.
The work will combine engineered cell-based reporter systems with advanced proximity labeling, protein engineering, and high-throughput functional screening to map the proteins selectively partitioned into oncofusion-driven condensates and to dissect the sequence features that drive transcriptional hyperactivation. By comparing wild-type IDRs, oncogenic IDRs, and engineered variants that gain or lose activity, the team will establish how amino acid composition and patterning encode selective recruitment of transcriptional machinery. This work provides the first systematic platform for interrogating the molecular logic of dynamic multivalent interactions that govern oncogenic condensates. The resulting mechanistic insights are expected to reveal new vulnerabilities intrinsic to oncofusion IDRs, opening the door to targeted therapeutic strategies for a wide class of cancers driven by disordered fusion proteins.