Australian researchers have used a new CRISPR activation tool to identify a previously unknown gene involved in resistance to a widely used blood cancer drug, as well as several genes linked to accelerated lymphoma growth.
Researchers from the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI and Genentech used the clustered regularly interspaced short palindromic repeats (CRISPR) activation tool, called Partita, with a mouse model of aggressive lymphoma.
Partita is a guide RNA library that allows every gene in the mouse genome to be switched on one at a time in cellular and live models. Unlike traditional CRISPR, which can be used to delete specific genes, CRISPR activation enables researchers to activate genes and investigate their roles in cancer and other genetic disorders.
The researchers found that switching on a gene called Irx5 allowed cancer cells to survive venetoclax, a widely used blood cancer drug, by increasing levels of another survival protein.
Senior author and La Trobe University School of Cancer Medicine head Professor Marco Herold said treatment resistance could occur when genes were unregulated.
“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.”
The researchers said identifying genes responsible for treatment resistance could support the development of therapies designed to silence those genes and improve the effectiveness of existing treatments.
The team also used Partita in vivo to identify Runx2, Runx3 and Csf1r as genes that accelerated MYC-driven lymphoma when activated.
ONJCRI and WEHI postdoctoral researcher Dr Eddie La Marca said the tool could help identify further targets in difficult-to-treat lymphomas.
“Currently, MYC-driven lymphomas are challenging to treat, and Partita helped find cancer-promoting genes that could be switched off to slow or stop tumour growth in these cancers,” Dr La Marca said.
The research was published in Science Advances.
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