NAB2-STAT6 Fusion Proteins Drive Nuclear Condensate Formation and Transcriptional Reprogramming in Solitary Fibrous Tumors

Li, Y.; Mondaza-Hernandez, J. L.; Pulivendala, G.; Elsenduny, F.; Beckedorff, F.; Lavezzo, G. M.; Azad, F. V.; Zhou, Z.; Warren, J.; Trevino, P. I.; Meyer, C. A.; Lombard, D.; Martin-Broto, J.; Moura, D. S.; Hayenga, H. N.; Bleris, L.

doi:10.1101/2025.08.07.668994

bioRxiv · 10.1101/2025.08.07.668994

NAB2-STAT6 Fusion Proteins Drive Nuclear Condensate Formation and Transcriptional Reprogramming in Solitary Fibrous Tumors

Li, Y.·Mondaza-Hernandez, J. L.·Pulivendala, G.·Elsenduny, F.·Beckedorff, F.·Lavezzo, G. M.·Azad, F. V.·Zhou, Z.·Warren, J.·Trevino, P. I.·Meyer, C. A.·Lombard, D.·Martin-Broto, J.·Moura, D. S.·Hayenga, H. N.·Bleris, L.

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Abstract

Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2-STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4-STAT6ex2 fusion variant forms nuclear condensates via liquid-liquid phase separation (LLPS) in engineered fibroblast models and primary SFT cells. These condensates co-localize with BRD4S and EGR1, key transcriptional regulators, and are functionally active, driving widespread transcriptional reprogramming. Treatment with Mithramycin A, a compound that disrupts EGR1-DNA interactions, dissolves NAB2-STAT6 condensates and reverses their aberrant gene expression and chromatin binding signatures. Our findings uncover a previously unrecognized role for NAB2-STAT6 in condensate-mediated oncogenic signaling and provide a mechanistic rationale for condensate-targeted therapy in SFT.

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Li, Y., Mondaza-Hernandez, J. L., Pulivendala, G., Elsenduny, F., Beckedorff, F., Lavezzo, G. M., Azad, F. V., Zhou, Z., Warren, J., Trevino, P. I., Meyer, C. A., Lombard, D., Martin-Broto, J., Moura, D. S., Hayenga, H. N., Bleris, L.. 2025-08-10. NAB2-STAT6 Fusion Proteins Drive Nuclear Condensate Formation and Transcriptional Reprogramming in Solitary Fibrous Tumors. https://doi.org/10.1101/2025.08.07.668994

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