A new genome-wide CRISPR activation library has uncovered a previously unknown mechanism of venetoclax resistance and identified genes that accelerate MYC-driven lymphoma.
Australian researchers have switched on thousands of genes to expose potential new drivers of treatment resistance and lymphoma growth, including a previously unknown route by which cancer cells can escape venetoclax.
Researchers from the Olivia Newton-John Cancer Research Institute, WEHI and Genentech used a new CRISPR activation library, dubbed Partita, which allows every gene in the mouse genome to be activated individually in cellular and live models.
Unlike conventional CRISPR approaches that knock genes out to investigate their function, CRISPR activation – or CRISPRa – turns genes on, allowing researchers to investigate what happens when their expression increases.
Their research was published in Science Advances.
Using Partita in a mouse model of aggressive lymphoma, the researchers found that activation of the transcription factor gene Irx5 enabled cancer cells to survive treatment with venetoclax by increasing levels of another survival protein.
The finding points to a previously unrecognised mechanism of resistance to venetoclax, which targets the anti-apoptotic protein BCL-2 and is used across several haematological malignancies.
Senior author Professor Marco Herold, head of the La Trobe University School of Cancer Medicine, said dysregulated gene expression was an important contributor to treatment resistance, including following 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,” he said.
The researchers said identifying genes capable of driving resistance could ultimately reveal therapeutic targets that could be inhibited to improve the effectiveness of existing treatments.
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The team also put Partita to work in vivo, identifying Runx2, Runx3 and Csf1r as genes that accelerated MYC-driven lymphoma when activated.
Dr Eddie La Marca, a postdoctoral researcher at ONJCRI and WEHI and senior author of the study, said the findings could help uncover new vulnerabilities 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,” he said.
The researchers said the broader value of Partita was its capacity to systematically investigate the effects of gene activation across the genome, complementing conventional CRISPR loss-of-function screens and potentially exposing mechanisms of cancer progression and treatment resistance that would otherwise remain hidden.
