Fadimana Kaya Fadimana Kaya Findlay Bewicke-Copley Findlay Bewicke-Copley Juho Miettinen Juho Miettinen Pedro Izquierdo Pedro Izquierdo Eve Leddy Eve Leddy Ozgen Deniz Ozgen Deniz Vincent-Philippe Lavallee Vincent-Philippe Lavallee Celine Philippe Celine Philippe Jiexin Zheng Jiexin Zheng Florian Grebien Florian Grebien Naeem Khan Naeem Khan Szilvia Krizsán Szilvia Krizsán Joseph Saad Joseph Saad Alexis Nolin-Lapalme Alexis Nolin-Lapalme Josee Hebert Josee Hebert Sebastien Lemieux Sebastien Lemieux Eric Audemard Eric Audemard Janet Matthews Janet Matthews Marianne Grantham Marianne Grantham Doriana Di Bella Doriana Di Bella Krister Wennerberg Krister Wennerberg Alun Parsons Alun Parsons John G. Gribben John G. Gribben James D. Cavenagh James D. Cavenagh S. D. Freeman S. D. Freeman Csaba Bodor Csaba Bodor Guy Sauvageau Guy Sauvageau Jun Wang Jun Wang Pilar Llamas-Sillero Pilar Llamas-Sillero Jean-Baptiste Cazier Jean-Baptiste Cazier David C. Taussig David C. Taussig Dominique Bonnet Dominique Bonnet Pedro R. Cutillas Pedro R. Cutillas Caroline A. Heckman Caroline A. Heckman Jude Fitzgibbon Jude Fitzgibbon Kevin Rouault-Pierre Kevin Rouault-Pierre Ana Rio-Machin Ana Rio-Machin Springer 2025 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. PDFDocument eng 2025-11-25T14:40:24.460592Z 2025 Acute Myeloid Leukaemia Oncogenes 2377372 b application/pdf http://creativecommons.org/licenses/by/4.0/