CRISPR activation library uncovers gene driving lymphoma growth and resistance

Researchers have uncovered a previously unknown gene causing resistance to a leading blood cancer drug and several genes that accelerate lymphoma growth by using a powerful new CRISPR activation library.

Traditional CRISPR is a genetic engineering tool that allows scientists to easily delete specific genes in an organism's DNA and assess their role and importance. It has become a cornerstone technology in cancer research.

A newer frontier is CRISPR activation, a technique that enables the activation of specific genes. It offers incredibly valuable insights into the roles of certain genes in cancer and other genetic disorders.

A team of researchers from the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI, and Genentech, a member of the Roche Group, used a new CRISPR activation tool called Partita and combined it with a mouse model of aggressive lymphoma.

Partita is a "library" that allows every gene in the mouse genome to be switched on, one at a time, in cellular and live models.

A significant challenge in cancer care is treatment resistance. The team found that by switching on a gene called Irx5, cancer cells were able to survive venetoclax, a widely used blood cancer drug, by quietly boosting levels of a different survival protein.

Prof Marco Herold, senior author of the paper published in Science Advances today and head of the La Trobe University School of Cancer Medicine, shared:

"We know that many therapy resistance issues happen because of genes being unregulated, even after the most successful treatments like targeted therapies and CAR T-cell therapy.

"With Partita, we found the usual genetic suspects mediating resistance, but also many others that represent potential new treatment options."

By identifying genes responsible for treatment resistance in tumors, researchers can develop new therapies to silence these genes and boost the efficacy of existing treatments.

The team also used Partita in vivo and identified Runx2, Runx3, and Csf1r as genes that accelerate MYC-driven lymphoma when activated.

Dr Eddie La Marca, postdoctoral researcher at ONJCRI and senior author of the paper, said:

"Currently, MYC-driven lymphomas are challenging to treat, and Partita helped find cancer-promoting genes that could be switched off to slow or stop tumor growth in these cancers."

Lymphoma comprises more than 80 subtypes and is widely recognized as the most common blood cancer in adults.