Kaya Fadimana, Bewicke-Copley Findlay, Miettinen Juho J, Casado Pedro, Leddy Eve, Deniz Özgen, Lavallée Vincent-Philippe, Philippe Celine, Zheng Jiexin, Grebien Florian, Khan Naeem, Krizsán Szilvia, Saad Joseph, Nolin-Lapalme Alexis, Hébert Josée, Lemieux Sébastien, Audemard Eric, Matthews Janet, Grantham Marianne, Di Bella Doriana, Wennerberg Krister, Parsons Alun, Gribben John, Cavenagh James D, Freeman Sylvie D, Bödör Csaba, Sauvageau Guy, Wang Jun, Llamas-Sillero Pilar, Cazier Jean-Baptiste, Taussig David C, Bonnet Dominique, Cutillas Pedro R, Heckman Caroline A, Fitzgibbon Jude, Rouault-Pierre Kevin, Rio-Machin Ana
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Institute for Molecular Medicine Finland-FIMM, HiLIFE-Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
Leukemia. 2025 Apr 9. doi: 10.1038/s41375-025-02593-8.
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.
t(6;9)(p22.3;q34.1)易位/DEK::NUP214融合蛋白定义了一类独特的年轻急性髓系白血病（AML）患者亚组，世界卫生组织将其归类为一种独立的疾病实体。DEK是一种具有多种功能的核因子，包括基因调控，而其融合伴侣NUP214通过与XPO1等转运受体相互作用在核输出中起关键作用。然而，DEK::NUP214驱动白血病的确切机制仍不清楚。对57例AML原发样本进行的全面多组学比较（包括全基因组测序、靶向测序、转录组学以及用500多种化合物进行药物筛选）显示，t(6;9)病例对XPO1抑制剂（塞利尼索和埃坦尼索）表现出选择性反应，并具有以关键白血病介质FOXC1和HOX基因过表达为特征的独特转录组特征。CUT&RUN实验证明DEK::NUP214直接结合到FOXC1和HOXA/B基因簇的启动子上。令人惊讶的是，在t(6;9)细胞中，XPO1抑制后这些基因的表达以及DEK::NUP214与其调控区域的结合被选择性降低。总之，这些结果确定了DEK::NUP214作为关键白血病驱动因子的XPO1依赖性转录激活因子的新功能，并为在该患者群体中探索使用XPO1抑制剂提供了理论依据。
