CRISPR activation identifies lymphoma resistance and growth genes

A high-density CRISPR activation library called Partita identified a previously unknown gene, Irx5, that helps lymphoma cells survive venetoclax, according to a peer-reviewed experimental study published in Science Advances. Researchers from the Olivia Newton-John Cancer Research Institute, WEHI and Genentech also found that activating three genes—Runx2, Runx3 and Csf1r—accelerated tumor growth in a mouse model of MYC-driven aggressive lymphoma. The work provides a systematic way to switch on individual mouse genes and examine their contributions to treatment resistance and cancer progression, although the findings were obtained in experimental models rather than in patients.

Partita is a guide RNA library designed to activate genes, extending CRISPR beyond the more familiar use of deleting selected genes. In the study, the researchers used the library to switch on genes one at a time in cellular assays and live mouse models. This strategy allowed them to investigate the effects of increased gene activity in lymphoma cells both outside the body and in vivo. The publication describes the platform as a method for mapping cancer dependencies and two resistance pathways, while the broader aim was to identify genes that could explain why malignant cells persist under treatment or grow more rapidly.

In the resistance experiments, activating Irx5 enabled cancer cells to survive exposure to venetoclax, a widely used blood cancer drug. The research report attributes this effect to Irx5 quietly increasing the levels of a separate survival protein. The experiments therefore identify a genetic state associated with resistance to venetoclax in the studied lymphoma model. They do not establish that targeting Irx5 would improve outcomes in people with blood cancer, and the study did not test such a treatment. The authors said Partita recovered known genetic factors involved in resistance as well as additional genes that may represent new intervention targets. They also proposed that identifying genes that become dysregulated during therapy could eventually support strategies designed to suppress those genes and restore the effectiveness of existing treatments, but that remains an objective rather than a demonstrated clinical result of this study.

Partita was also used in vivo to examine MYC-driven lymphoma, a cancer that the research team described as challenging to treat. By activating individual genes in the mouse model, the researchers identified Runx2, Runx3 and Csf1r as genes whose activation accelerated lymphoma growth. The authors describe these as cancer-promoting genes that could, in principle, be switched off to slow or stop tumor growth in this experimental setting. The study did not test a corresponding intervention in people or demonstrate a clinical benefit from inhibiting any of the three genes. Overall, the cellular and animal experiments show that Partita can uncover both an Irx5-linked venetoclax-resistance mechanism and three candidate growth-promoting genes in MYC-driven lymphoma, while the relevance of those findings for human treatment requires further validation. The study’s declared conflict-of-interest statement notes that some authors are current or former Genentech employees, where the Partita library was developed; the remaining authors reported no competing interests.

Subject of Research: Experimental CRISPR activation mapping of lymphoma drug resistance and growth genes

Article Title: Gene that drives blood cancer drug resistance uncovered with new CRISPR activation tool

Article References: Gene that drives blood cancer drug resistance uncovered with new CRISPR activation tool. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: CRISPR activation, Partita library, venetoclax resistance, lymphoma, Irx5, MYC-driven lymphoma, Runx2, Runx3, Csf1r, mouse models, Gene, drives