Abstract 7234: A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding hub

Abstract Mammalian SWI/SNF (BAF) chromatin remodeling complexes modulate DNA accessibility and gene expression, however, the mechanisms by which they are targeted on chromatin remain incompletely understood. Here, we define SWIFT (SWI/SNF Ig-Fold for Transcription Factor Interactions), found on the SMARCD family of subunits within the mSWI/SNF core module as an evolutionarily conserved, universal transcription factor (TF) binding platform. SWIFT is necessary and sufficient for direct interaction with the transactivation domain of a lineage-specific TF, PU.1, in vitro and in cells, with a single amino acid mutation in SWIFT able to disrupt PU.1-mSWI/SNF binding, inhibit site-specific complex targeting and activity, and attenuate oncogenic gene expression and proliferation of PU.1-dependent acute myeloid leukemia (AML) cancer cells. Further, dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF complexes and “poisons” TF-addicted cancer cells across different lineages. Finally, we uncover striking preferences of lineage-specific TFs for the SWIFT domains of specific SMARCD subunit paralogs. These SMARCD paralog-specific affinities of TFs align with their tissue- and differentiation state-specific expression patterns across human cells and tissues, suggesting that that switches in mSWI/SNF subunit composition fine-tune affinities for TFs that govern specialized cell state transitions during normal differentiation and tumorigenesis.In conclusion, this work unmasks a novel mSWI/SNF biochemical interface amenable to targeted therapeutic modulation in a diverse collection of transcriptionally addicted cancers. Citation Format: Siddhant U. Jain, Kaylyn E. Williamson, Alexander Ying, Aasha M. Turner, Jerry R. Jiang, Shaunak Raval, Kevin So, Maxwell J. Allison, Akshay Sankar, Daniel Guerra, Nazar Mashtalir, Henry H. Rohrs, Cheryl F. Lichti, Malvina Papanastasiou, Joao A. Paulo, Steven Gygi, Michael L. Gross, Cigall Kadoch. A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding hub [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7234.