Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; Department of Stem Cell Biology and Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Cancer Cell. 2018 Mar 12;33(3):386-400.e5. doi: 10.1016/j.ccell.2018.01.012. Epub 2018 Feb 22.
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.
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，随后在体内进行了第二次筛选。在这里，我们表明 mRNA 去帽酶清除剂（DCPS）基因对于 AML 细胞的存活是必需的。通过质谱分析，发现 DCPS 酶与包括剪接体在内的前体 mRNA 代谢途径的成分相互作用。RG3039 是一种最初开发用于治疗脊髓性肌萎缩症的 DCPS 抑制剂，通过诱导前体 mRNA 的错误剪接表现出抗白血病活性。携带双等位基因胚系 DCPS 功能丧失突变的人类并未表现出异常的血液表型，表明 DCPS 对于人类造血是可有可无的。我们的发现揭示了一个前体 mRNA 代谢途径，并将 DCPS 鉴定为 AML 治疗的靶点。
