SF3B1突变经常发生在癌症中，但缺乏靶向治疗。 XPO1 抑制剂 selinexor 和 eltanexor 在高危骨髓增生异常肿瘤 (MDS) 中的临床试验显示，反应者富含 SF3B1 突变。鉴于 XPO1 (Exportin-1) 是负责蛋白质和多种 RNA 种类输出的核输出蛋白，这导致了这样的假设：SF3B1 突变细胞对 XPO1 抑制敏感，可能是由于剪接改变所致。在 SF3B1 野生型和突变细胞中抑制 XPO1 后的后续 RNA 测序显示，SF3B1 突变细胞中 RNA 转录物的核保留增加，选择性剪接增加，特别是影响细胞凋亡途径的基因。为了确定与 XPO1 抑制协同的新型药物组合，使用 eltanexor 治疗进行了正向遗传筛选，涉及抗凋亡靶标 BCL2 和 BCLXL，并通过体外和体内功能测试进行了验证。使用Sf3b1K700E条件敲入小鼠对这些靶点进行体内测试，结果表明eltanexor和venetoclax（BCL2抑制剂）的组合对SF3B1突变细胞具有优先敏感性，且没有过度毒性。在这项研究中，我们揭示了 SF3B1 突变型 MDS 中对 XPO1 抑制敏感的机制，并在临床前合理化了 eltanexor 和 Venetoclax 组合治疗高危 MDS 的方法。© 2024。作者。

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.© 2024. The Author(s).