DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes

Kaya, F.; Bewicke-Copley, F.; Miettinen, J. J.; Casado, P.; Leddy, E.; Deniz, O.; Lavallee, V.-P.; Philippe, C.; Zheng, J.; Grebien, F.; Khan, N.; Krizsan, S.; Saad, J.; Nolin-Lapalme, A.; Lemieux, S.; Audemard, E. O.; Matthews, J.; Grantham, M.; Di Bella, D.; Wennerberg, K.; Parsons, A.; Rio-Machin, A.; Gribben, J.; Cavenagh, J. D.; Freeman, S. D.; Bodor, C.; Sauvageau, G.; Wang, J.; Llamas-Sillero, P.; Cazier, J.-B.; Taussig, D. C.; Bonnet, D.; Cutillas, P. R.; Heckman, C.; Fitzgibbon, J.; Rouault-Pierre, K.

doi:10.1101/2025.03.05.641116

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bioRxiv · 10.1101/2025.03.05.641116

DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes

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Abstract

The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with > 500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.

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Kaya, F., Bewicke-Copley, F., Miettinen, J. J., Casado, P., Leddy, E., Deniz, O., Lavallee, V.-P., Philippe, C., Zheng, J., Grebien, F., Khan, N., Krizsan, S., Saad, J., Nolin-Lapalme, A., Lemieux, S., Audemard, E. O., Matthews, J., Grantham, M., Di Bella, D., Wennerberg, K., Parsons, A., Rio-Machin, A., Gribben, J., Cavenagh, J. D., Freeman, S. D., Bodor, C., Sauvageau, G., Wang, J., Llamas-Sillero, P., Cazier, J.-B., Taussig, D. C., Bonnet, D., Cutillas, P. R., Heckman, C., Fitzgibbon, J., Rouault-Pierre, K.. 2025-03-07. DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes. https://doi.org/10.1101/2025.03.05.641116

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