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Nature Papers Present CRISPR-Cas3 System to Make Large Genomic Deletions, Molecular Mechanisms of Chemoresistance in ALL

A CRISPR-Cas3 system capable of making large genomic deletions with high efficiency is described in Nature Methods this week. Scientists from the University of California, San Francisco, repurposed and optimized a Type I-C CRISPR system from Pseudomonas aeruginosa to enable endogenous and heterologous genome engineering in microbial species. With the system, DNA cleavage guided by a single CRISPR RNA can generate deletions as large as 424 kilobases with nearly 100 percent efficiency. Cas3, meanwhile, was found to generate bidirectional deletions relative to the CRISPR RNA target site, demonstrating the ability of the system to induce large genomic deletions surrounding a programmed target site. "Using Cas3 to make large genomic deletions will facilitate the manipulation of repetitive and noncoding regions, having a broad impact on genetics research by providing a tool to probe genomes en masse," the researchers write.

By combining genome-wide mutation analysis and CRISPR screening, a team led by scientists from Columbia University have uncovered molecular mechanisms behind chemoresistance in acute lymphoblastic leukemia (ALL). ALL can often be cured with combination chemotherapy, yet patients whose disease relapses have a very poor prognosis. To better understand this, the investigators performed a genome-wide mutation analysis of matched diagnosis, germline, and relapse DNA samples from a panel of 175 pediatric and adult ALL patients treated with multiagent chemotherapy combinations. This was followed by a genome-wide CRISPR screen analysis of gene/drug interactions across seven ALL chemotherapy drugs. As described in Nature Cancer, these two analyses reveal diagnostic and relapse-specific mutational mechanisms, as well as genetic drivers of chemoresistance. The data point to common and drug-specific pathways modulating chemotherapy response and underscore the effect of drug combinations in restricting the selection of resistance-driving genetic lesions, the researchers write. By uncovering actionable targets for reversing chemotherapy resistance, the findings also provide new therapeutic opportunities for ALL.