TY - JOUR
T1 - DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes
AU - Kaya, Fadimana
AU - Bewicke-Copley, Findlay
AU - Miettinen, Juho J.
AU - Casado, Pedro
AU - Leddy, Eve
AU - Deniz, Özgen
AU - Lavallée, Vincent Philippe
AU - Philippe, Celine
AU - Zheng, Jiexin
AU - Grebien, Florian
AU - Khan, Naeem
AU - Krizsán, Szilvia
AU - Saad, Joseph
AU - Nolin-Lapalme, Alexis
AU - Hébert, Josée
AU - Lemieux, Sébastien
AU - Audemard, Eric
AU - Matthews, Janet
AU - Grantham, Marianne
AU - Di Bella, Doriana
AU - Wennerberg, Krister
AU - Parsons, Alun
AU - Gribben, John
AU - Cavenagh, James D.
AU - Freeman, Sylvie D.
AU - Bödör, Csaba
AU - Sauvageau, Guy
AU - Wang, Jun
AU - Llamas-Sillero, Pilar
AU - Cazier, Jean Baptiste
AU - Taussig, David C.
AU - Bonnet, Dominique
AU - Cutillas, Pedro R.
AU - Heckman, Caroline A.
AU - Fitzgibbon, Jude
AU - Rouault-Pierre, Kevin
AU - Rio-Machin, Ana
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
U2 - 10.1038/s41375-025-02593-8
DO - 10.1038/s41375-025-02593-8
M3 - Letter
C2 - 40204893
AN - SCOPUS:105002297014
SN - 0887-6924
VL - 39
JO - Leukemia
JF - Leukemia
IS - 6
M1 - 440
ER -