Targeting leukemia-specific dependence on the de novo purine synthesis pathway.

Abstract

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.

• Authors: Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Masatomo Takahashi, Yoshihiro Izumi, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki, Luca Pinello, Daniel E Bauer, Takeshi Bamba, Koichi Akashi, Takahiro Maeda
• Journal: Leukemia (Leukemia) Vol. 36 Issue 2 Pg. 383-393 (02 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 34344987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Enzyme Inhibitors
• Purines
• Carboxy-Lyases
• phosphoribosylaminoimidazole carboxylase

Topics

• Animals
• Apoptosis
• CRISPR-Cas Systems
• Carboxy-Lyases (antagonists & inhibitors)
• Cell Proliferation
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Genome-Wide Association Study
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Purines (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays