Novel CRISPR activation sgRNA libraries identify tumour essential genes, therapy resistance genes, and cancer oncogenes

However, a lack of scalable, high-coverage tools has limited comprehensive genetic screening in murine models. Here, we introduce Partita, a next-generation mouse whole-genome CRISPRa sgRNA platform, designed for unparalleled efficiency in gene activation studies.

Partita employs a high-density targeting strategy, deploying 10 sgRNAs per transcriptional start site, structured into five gene class-specific sub-libraries to maximise transcriptional induction. To demonstrate the capabilities of Partita, we performed a series of large-scale screens: an in vitro enrichment/depletion screen, whole-genome CRISPRa screens in a double-hit lymphoma model to uncover resistance factors to pro-apoptotic drugs (venetoclax, nutlin-3a, etoposide), and an in vivo screen to identify accelerators of MYC-driven lymphomagenesis.