Transcriptional Constraint Of EWS/FLI Promotes Ewing Sarcoma

Abstract

Pediatric cancers are fundamentally epigenetic diseases of dysregulated development and harbor few mutations in genes involved in immediately druggable pathways. Recently, the hijacking of cell type-specific transcription factors to participate in self-amplifying transcriptional circuits has garnered intense focus as a broadly relevant mechanism of transcriptional addiction that can be therapeutically targeted. However, it is not known whether this specific type of transcriptional circuitry is indeed critical in all pediatric cancers. Here, we describe an intriguing alternative but equally central transcriptional mechanism promoting the growth of Ewing sarcoma tumors. We discover that ETV6, a repressive transcription factor, is a novel and profound dependency specific to this tumor type because it, counter-intuitively, constrains the transcriptional activity of EWS/FLI, the fusion transcription factor that hallmarks Ewing sarcoma tumors. We demonstrate that the antagonistic activities of ETV6 and EWS/FLI on chromatin are functionally relevant because deletion of a co-regulated gene target rescues ETV6 dependency. Additionally, we observe that, unlike transcription factor dependencies in other pediatric cancers, ETV6 does not exhibit a pattern of expression specific to Ewing sarcoma tumors, highlighting the need to conduct unbiased functional studies to reveal context-specific disease biology, even in categorically similar diseases. Ultimately, this work discovers that constraint of a fusion oncogenic transcription factor on chromatin can promote cancer. Future work may characterize the specific epigenetic enzymes that mediate and modulate ETV6 activity in Ewing sarcoma to highlight potential novel therapeutic strategies.