Selinexor 是一种一流的输出蛋白 1 (XPO1) 抑制剂，由于其独特的作用机制，是一种有吸引力的抗肿瘤药物；然而，其剂量依赖性毒性和缺乏生物标志物阻碍了其在临床应用中的广泛应用。为了确定调节 selinexor 敏感性的关键分子/途径，我们使用两个 B-ALL 系进行了全基因组 CRISPR/Cas9 缺失筛选。我们首次发现旁系同源 DDX19A 和 DDX19B RNA 解旋酶通过调节 MCL1 mRNA 核输出来调节 selinexor 敏感性。虽然单次去除 DDX19A 或 DDX19B 几乎不会改变 MCL1 蛋白水平，但两者的去除都会显着减弱 MCL1 mRNA 核输出，从而降低 MCL1 蛋白水平。重要的是，将 selinexor 治疗与 DDX19A 或 DDX19B 耗竭相结合，可显着诱导白血病细胞的内在凋亡，这是 MCL1 过表达所挽救的效果。 Depmap 数据集的分析表明 T-ALL 细胞系的子集表达最低的 DDX19B mRNA 水平。此外，我们发现 selinexor 治疗或 DDX19A 耗竭可有效诱导表达低 DDX19B 水平的 T-ALL 系细胞凋亡。我们得出结论，XPO1 和 DDX19A/B 协调调节细胞 MCL1 水平，并提出 DDX19A/B 可以作为 selinexor 治疗的生物标志物。此外，DDX19旁系同源物的药理学靶向可能代表了诱导白血病细胞内在细胞凋亡的潜在策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.