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<p>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 &gt;500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor &amp; Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of <i>FOXC1</i> and <i>HOX</i> genes that are key leukemia mediators. CUT&amp;RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of <i>FOXC1</i> and <i>HOXA/B</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月9日

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  • Fadimana Kaya,
  • Findlay Bewicke-Copley,
  • Juho J. Miettinen,
  • Pedro Casado,
  • Eve Leddy,
  • Özgen Deniz,
  • Vincent-Philippe Lavallée,
  • Celine Philippe,
  • Jiexin Zheng,
  • Florian Grebien,
  • Naeem Khan,
  • Szilvia Krizsán,
  • Joseph Saad,
  • Alexis Nolin-Lapalme,
  • Josée Hébert,
  • Sébastien Lemieux,
  • Eric Audemard,
  • Janet Matthews,
  • Marianne Grantham,
  • Doriana Di Bella,
  • Krister Wennerberg,
  • Alun Parsons,
  • John Gribben,
  • James D. Cavenagh,
  • Sylvie D. Freeman,
  • Csaba Bödör,
  • 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

摘要

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.