Testo Articolo di rivista Text journal article Acute Myeloid Leukaemia Oncogenes Fadimana Kaya Findlay Bewicke-Copley Juho Miettinen Pedro Izquierdo Eve Leddy Ozgen Deniz Vincent-Philippe Lavallee Celine Philippe Jiexin Zheng Florian Grebien Naeem Khan Szilvia Krizsán Joseph Saad Alexis Nolin-Lapalme Josee Hebert Sebastien Lemieux Eric Audemard Janet Matthews Marianne Grantham Doriana Di Bella Krister Wennerberg Alun Parsons John G. Gribben James D. Cavenagh S. D. Freeman Csaba Bodor Guy Sauvageau Jun Wang Pilar Llamas-Sillero Jean-Baptiste Cazier David C. Taussig Dominique Bonnet Pedro R. Cutillas Caroline A. Heckman Jude Fitzgibbon Kevin Rouault-Pierre Ana Rio-Machin application/pdf eng DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes 2025 Nature Publishing Group Copyright © 2025, The Author(s) open access doi:10.1038/s41375-025-02593-8 Text Wissenschaftlicher Artikel Springer http://creativecommons.org/licenses/by/4.0/ 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. https://phaidra.vetmeduni.ac.at/o:4612