Tandem duplications in UBTF create XPO1-dependent nuclear export signals necessary for leukemic progression [scRNA-seq]

UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs. scRNA-seq data

UBTF串联重复（UBTF tandem duplications, UBTF-TD）是一类临床预后极差的高风险急性髓系白血病（acute myeloid leukemia, AML）分子亚型。尽管Menin抑制剂（menin inhibitors）已展现出治疗潜力，但获得性耐药仍是亟待解决的重大临床挑战。本研究通过蛋白质组学、基因组学与功能分析，揭示UBTF-TD介导的白血病发生机制。研究发现，UBTF-TD可形成核输出信号（nuclear export signal, NES）基序，该基序介导UBTF-TD蛋白与输出蛋白1（Exportin-1, XPO1）及染色质结合伴侣的相互作用。上述相互作用可驱动UBTF-TD相关肿瘤中常见失调基因（包括HOXA/HOXB基因簇）的异常染色质结合与转录激活。本研究证实，此类NES基序对UBTF-TD蛋白的错误定位、细胞转化及转录失调均至关重要。值得关注的是，本研究鉴定出XPO1抑制剂埃坦奈索（eltanexor）作为潜在治疗策略。在临床前模型中，埃坦奈索可破坏UBTF-TD蛋白的染色质定位、降低肿瘤负荷并促进细胞分化。本研究为UBTF-TD驱动的白血病发生机制提供了深入解析，并凸显XPO1抑制作为UBTF-TD型AML的极具潜力的治疗方向。单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据。