DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.
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Embargo End Date
ICR Authors
Authors
Kaya, F
Bewicke-Copley, F
Miettinen, JJ
Casado, P
Leddy, E
Deniz, Ö
Lavallée, V-P
Philippe, C
Zheng, J
Grebien, F
Khan, N
Krizsán, S
Saad, J
Nolin-Lapalme, A
Hébert, J
Lemieux, S
Audemard, E
Matthews, J
Grantham, M
Di Bella, D
Wennerberg, K
Parsons, A
Gribben, J
Cavenagh, JD
Freeman, SD
Bödör, C
Sauvageau, G
Wang, J
Llamas-Sillero, P
Cazier, J-B
Taussig, DC
Bonnet, D
Cutillas, PR
Heckman, CA
Fitzgibbon, J
Rouault-Pierre, K
Rio-Machin, A
Bewicke-Copley, F
Miettinen, JJ
Casado, P
Leddy, E
Deniz, Ö
Lavallée, V-P
Philippe, C
Zheng, J
Grebien, F
Khan, N
Krizsán, S
Saad, J
Nolin-Lapalme, A
Hébert, J
Lemieux, S
Audemard, E
Matthews, J
Grantham, M
Di Bella, D
Wennerberg, K
Parsons, A
Gribben, J
Cavenagh, JD
Freeman, SD
Bödör, C
Sauvageau, G
Wang, J
Llamas-Sillero, P
Cazier, J-B
Taussig, DC
Bonnet, D
Cutillas, PR
Heckman, CA
Fitzgibbon, J
Rouault-Pierre, K
Rio-Machin, A
Document Type
Journal Article
Date
2025-06-01
Date Accepted
2025-03-26
Abstract
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.
Citation
Leukemia, 2025, 39 (6), pp. 1526 - 1531
Source Title
Leukemia
Publisher
SPRINGERNATURE
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Acute Leukaemia