Charles Cano Fiorella, Kloos Arnold, Hebalkar Rucha Y, Plenge Thomas, Geffers Robert, Kirchhoff Hanna, Kattre Nadine, Görlich Kerstin, Büsche Guntram, Shcherbata Halyna R, Scherr Michaela, Döhner Konstanze, Gabdoulline Razif, Heuser Michael
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany.
Leukemia. 2025 May;39(5):1102-1113. doi: 10.1038/s41375-025-02570-1. Epub 2025 Mar 27.
The nuclear export protein XPO1 interacts with nucleoporin 214 (NUP214) and has been implicated in the pathogenesis of SET::NUP214 acute myeloid leukemia (AML). We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1. Pharmacologic inhibition of XPO1 by the second-generation selective inhibitor of nuclear export, eltanexor, in primary human and FKH-1 cells reduced XPO1 expression, disrupted co-localization of XPO1 and DN, and induced apoptosis and cell cycle arrest. Functionally, XPO1 and DN co-localized at chromatin, and this co-localization was strongly reduced by XPO1 inhibition. Loss of chromatin binding resulted in downregulation of DN target genes and pathways related to cell cycle and self-renewal. Eltanexor treatment of a patient-derived DN-AML xenograft model disrupted leukemia development, showing molecular clearance in bone marrow after a median of 377 days in eltanexor-treated mice, while control mice succumbed after a median of 244 days. In summary, XPO1 stabilizes DN at chromatin to allow the activation of its oncogenic gene signature, while targeting XPO1 treats leukemia successfully in vivo. These findings establish XPO1 as a molecular target in DEK::NUP214 AML.
核输出蛋白XPO1与核孔蛋白214（NUP214）相互作用，并与SET::NUP214急性髓系白血病（AML）的发病机制有关。我们在人类AML模型中评估了DEK::NUP214（DN）（一种独特的AML实体）对XPO1的依赖性。在DN阳性的FKH-1细胞中删除XPO1显示出对XPO1的强烈依赖性。第二代核输出选择性抑制剂eltanexor对原发性人类细胞和FKH-1细胞中XPO1的药理抑制作用降低了XPO1的表达，破坏了XPO1与DN的共定位，并诱导了细胞凋亡和细胞周期停滞。在功能上，XPO1和DN在染色质上共定位，而这种共定位在XPO1受到抑制时显著减少。染色质结合的丧失导致DN靶基因以及与细胞周期和自我更新相关的信号通路下调。用eltanexor治疗患者来源的DN-AML异种移植模型可破坏白血病的发展，在eltanexor治疗的小鼠中，骨髓中的分子清除在中位377天后出现，而对照小鼠在中位244天后死亡。总之，XPO1在染色质上稳定DN以激活其致癌基因特征，而靶向XPO1在体内可成功治疗白血病。这些发现确立了XPO1作为DEK::NUP214 AML中的分子靶点。
