Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan.
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan.
Leukemia. 2022 Feb;36(2):383-393. doi: 10.1038/s41375-021-01369-0. Epub 2021 Aug 3.
Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
急性髓细胞白血病（AML）是一种毁灭性疾病，临床结果仍远未令人满意。在这里，为了确定 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，然后在体内进行了第二次筛选。我们表明，参与从头嘌呤生物合成的酶 PAICS 是 AML 治疗的潜在靶点。表达 shRNA-PAICS 的 AML 细胞表现出生长劣势，表明 shRNA-PAICS 具有毒性作用。PAICS 抑制剂处理人 AML 细胞可通过抑制 DNA 合成和促进细胞凋亡来抑制其增殖，在 AML PDX 模型中具有抗白血病作用。此外，在存在抑制剂的情况下使用 AML 细胞进行的 CRISPR/Cas9 筛选揭示了介导对 PAICS 抑制的耐药性或合成致死性的基因。我们的研究结果确定 PAICS 为 AML 的新型治疗靶点，并进一步定义了从头嘌呤合成途径及其对 AML 细胞存活至关重要的下游效应子的组成部分。
