CRISPR Identifies Novel Therapeutic lncRNA for Myeloma

The team employed CRISPR-Cas9 technology to conduct an extensive and unbiased loss-of-function screen, systematically disrupting 671 lncRNAs in both drug-sensitive and bortezomib-resistant MM cell lines. By using pooled CRISPR screening, they were able to assess the role of these lncRNAs in tumour cell growth and survival, with RP11-350G8.5 emerging as a particularly strong target.

The CRISPR system was instrumental in precisely knocking out genes, allowing the researchers to reveal the essentiality of RP11-350G8.5 for MM cells. Functional studies showed that inhibiting RP11-350G8.5 triggered the unfolded protein response (UPR) and induced immunogenic cell death, offering a promising strategy for overcoming drug resistance.

In vivo studies using mouse models provided further evidence of RP11-350G8.5’s therapeutic potential. Mice xenografted with MM cells lacking RP11-350G8.5 showed significant reductions in tumour volume compared to controls. The CRISPR-mediated knockout of RP11-350G8.5 resulted in both slower tumour growth and decreased tumour mass over time.

Additionally, histological analyses confirmed a marked increase in apoptotic markers in the RP11-350G8.5-depleted tumours, reinforcing the in vitro findings of immunogenic cell death. Although performed on a limited number of animals, the in vivo experiments highlighted RP11-350G8.5’s critical role in MM progression and its potential as a target for future therapeutic interventions.

The study was led by Katia Grillone and Pierfrancesco Tassone from the University of Magna Græcia, Catanzaro, Italy, and it was published in Blood on 16th August.