Zeitschriftenaufsatz
|
2025
DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes
Autor:in
Kaya, Fadimana; Bewicke-Copley, Findlay; Miettinen, Juho; Izquierdo, Pedro; Leddy, Eve; Deniz, Ozgen; Lavallee, Vincent-Philippe; Philippe, Celine; Zheng, Jiexin; Grebien, Florian; Khan, Naeem; Krizsán, Szilvia; Saad, Joseph; Nolin-Lapalme, Alexis; Hebert, Josee; Lemieux, Sebastien; Audemard, Eric; Matthews, Janet; Grantham, Marianne; Di Bella, Doriana; Wennerberg, Krister; Parsons, Alun; Gribben, John G.; Cavenagh, James D.; FREEMAN, SD; Bodor, Csaba; Sauvageau, Guy; Wang, Jun; Llamas-Sillero, Pilar; Cazier, Jean-Baptiste; Taussig, David C.; Bonnet, Dominique; Cutillas, Pedro R.; Heckman, Caroline A.; Fitzgibbon, Jude; Rouault-Pierre, Kevin; RIO-MACHIN, ANA
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
HEMATOPOIETIC STEM
Dokumententyp
Letter
CC Lizenz
CCBY
Open Access Type
Hybrid
ISSN/eISSN
0887-6924 - 1476-5551
10.1038/s41375-025-02593-8
WoS ID
PubMed ID