https://phaidra.vetmeduni.ac.at/o:4612 DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes Kaya, Fadimana Fadimana Kaya Bewicke-Copley, Findlay Findlay Bewicke-Copley Miettinen, Juho Juho Miettinen Izquierdo, Pedro Pedro Izquierdo Leddy, Eve Eve Leddy Deniz, Ozgen Ozgen Deniz Lavallee, Vincent-Philippe Vincent-Philippe Lavallee Philippe, Celine Celine Philippe Zheng, Jiexin Jiexin Zheng Grebien, Florian Florian Grebien 0000-0003-4289-2281 University of Veterinary Medicine Vienna Khan, Naeem Naeem Khan Krizsán, Szilvia Szilvia Krizsán Saad, Joseph Joseph Saad Nolin-Lapalme, Alexis Alexis Nolin-Lapalme Hebert, Josee Josee Hebert Lemieux, Sebastien Sebastien Lemieux Audemard, Eric Eric Audemard Matthews, Janet Janet Matthews Grantham, Marianne Marianne Grantham Di Bella, Doriana Doriana Di Bella Wennerberg, Krister Krister Wennerberg Parsons, Alun Alun Parsons Gribben, John G. John G. Gribben Cavenagh, James D. James D. Cavenagh Freeman, S. D. S. D. Freeman Bodor, Csaba Csaba Bodor Sauvageau, Guy Guy Sauvageau Wang, Jun Jun Wang Llamas-Sillero, Pilar Pilar Llamas-Sillero Cazier, Jean-Baptiste Jean-Baptiste Cazier Taussig, David C. David C. Taussig Bonnet, Dominique Dominique Bonnet Cutillas, Pedro R. Pedro R. Cutillas Heckman, Caroline A. Caroline A. Heckman Fitzgibbon, Jude Jude Fitzgibbon Rouault-Pierre, Kevin Kevin Rouault-Pierre Rio-Machin, Ana Ana Rio-Machin Springer journal article open access eng 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. Acute Myeloid Leukaemia Oncogenes http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4612/download 10.1038/s41375-025-02593-8 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Nature Publishing Group issn:1476-5551 VoR Nature Publishing Group 39 6 2.27 MB 2025