To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.

中文翻译：

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全基因组 CRISPR-Cas9 筛选可识别白血病对 DCPS 调节的前 mRNA 代谢途径的特异性依赖性。

为了确定急性髓系白血病 (AML) 治疗的新靶点，我们使用 AML 细胞系进行了全基因组 CRISPR-Cas9 筛选，然后进行了第二次体内筛选。在这里，我们证明 mRNA 脱帽酶清除剂 (DCPS) 基因对于 AML 细胞的生存至关重要。质谱分析显示，DCPS 酶与前 mRNA 代谢途径的成分（包括剪接体）相互作用。RG3039 是一种 DCPS 抑制剂，最初开发用于治疗脊髓性肌萎缩症，通过诱导前 mRNA 错误剪接表现出抗白血病活性。携带种系双等位基因 DCPS 功能丧失突变的人类并未表现出异常的血液学表型，表明 DCPS 对于人类造血来说是可有可无的。我们的研究结果揭示了前 mRNA 代谢途径，并将 DCPS 确定为 AML 治疗的靶点。