Targeting leukemia-specific dependence on the de novo purine synthesis pathway
| Autor: | Kensuke Sasaki, Yoshihiro Izumi, Masatomo Takahashi, Yuichiro Semba, Takeshi Bamba, Takuji Yamauchi, Koichi Akashi, Fumihiko Nakao, Daniel E. Bauer, Kohta Miyawaki, Takahiro Maeda, Jumpei Nogami, Takeshi Sugio, Luca Pinello |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Carboxy-Lyases Apoptosis Mice SCID Biology Gene Expression Regulation Enzymologic Mice Mice Inbred NOD hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans CRISPR Enzyme Inhibitors neoplasms Cell Proliferation DNA synthesis Gene Expression Regulation Leukemic Cas9 Myeloid leukemia Hematology medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL De novo synthesis Leukemia Myeloid Acute Leukemia Oncology Purines Cell culture Cancer research CRISPR-Cas Systems Genome-Wide Association Study |
| Zdroj: | Leukemia. 36:383-393 |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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