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

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

doi:10.1038/s41375-025-02593-8

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Title (eng)

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

Author

Fadimana Kaya

Findlay Bewicke-Copley

Juho Miettinen

Pedro Izquierdo

Eve Leddy

Ozgen Deniz

Vincent-Philippe Lavallee

Celine Philippe

Jiexin Zheng

Florian Grebien

University of Veterinary Medicine Vienna

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

Abstract (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.

Keywords (eng)

Acute Myeloid LeukaemiaOncogenes

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4612

DOI

10.1038/s41375-025-02593-8

Is in series

Title (eng)