[Exploration of novel therapeutic targets in acute myeloid leukemia via genome-wide CRISPR screening].

Abstract

Acute myeloid leukemia (AML) remains a devasting disease. Progress has been made to define molecular mechanisms underlying disease pathogenesis due, in part, to the near-complete understanding of AML genome. Nonetheless, functional studies are necessary to assess the significance of AML-associated mutations and devise urgently needed therapies. Genome-wide knockout screening, employing CRISPR-Cas9 genome editing, is a powerful tool in functional genomics. In this study, genome-wide CRISPR screening was performed using mouse leukemia cell lines developed in our Center, followed by in vivo screening. Among 20,611 genes, 130 AML essential genes were identified, including clinically actionable candidates. It was shown that mRNA decapping enzyme scavenger (DCPS), an enzyme implicated in mRNA decay pathway, is essential for AML survival. ShRNA-mediated gene knockdown and DCPS inhibitor (RG3039) were employed to validate findings. RG3039 induced cell-cycle arrest and apoptosis in vitro. Furthermore, mass spectrometry analysis revealed an association between DCPS and RNA metabolic pathways, and RNA-Seq showed that RG3039 treatment induced aberrant mRNA splicing in AML cells. Importantly, RG3039 exhibited anti-leukemia effects in PDX models. These findings identify DCPS as a novel therapeutic target for AML, shedding new light on the nuclear RNA metabolic pathway in leukemogenesis.

• Authors: Takuji Yamauchi
• Journal: [Rinsho ketsueki] The Japanese journal of clinical hematology (Rinsho Ketsueki) Vol. 60 Issue 7 Pg. 810-817 ( 2019) ISSN: 0485-1439 [Print] Japan
• PMID: 31391371 (Publication Type: Journal Article)

Chemical References

• RNA, Small Interfering

Topics

• Animals
• CRISPR-Cas Systems
• Cell Line, Tumor
• Clustered Regularly Interspaced Short Palindromic Repeats
• Gene Editing
• Leukemia, Myeloid, Acute (genetics)
• Mice
• RNA Splicing
• RNA Stability
• RNA, Small Interfering