Article Dans Une Revue Leukemia Année : 2025

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

Pedro Casado
Eve Leddy
  • Fonction : Auteur
Özgen Deniz
Naeem Khan
Szilvia Krizsán
Alexis Nolin-Lapalme
Josée Hébert
Sebastien Lemieux
Eric Audemard
Janet Matthews
  • Fonction : Auteur
  • PersonId : 897369
Doriana Di Bella
  • Fonction : Auteur
John Gribben
Sylvie Freeman
Csaba Bödör
Jun Wang
David C Taussig
Pedro R Cutillas

Résumé

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.

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hal-05033002 , version 1 (14-04-2025)

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Fadimana Kaya, Findlay Bewicke-Copley, Juho J Miettinen, Pedro Casado, Eve Leddy, et al.. DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes. Leukemia, 2025, 39, pp.1526-1531. ⟨10.1038/s41375-025-02593-8⟩. ⟨hal-05033002⟩
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