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CRISPR screening tool exposes new leukaemia drug target

Posted: 29 September 2021 | | No comments yet

A CRISPR screening tool identified a new target for acute myeloid leukaemia with fewer side effects than current approaches.

Blood smear under microscopy showing acute myeloid leukaemia (AML)

A team at the University of Pennsylvania, US, have used a CRISPR-based screening tool to uncover a new therapeutic target to treat acute myeloid leukaemia (AML) that has the potential to leave patients with fewer side effects than current approaches.

The researchers used CRISPR to precisely disrupt the domain function of proteins in cancer cells, map their molecular functions and modify them to use in mouse models. They found that inhibiting the epigenetic reader function of a regulatory protein called ZMYND8 in mice left them with smaller tumours and better survival.

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“We have discovered that cancer cells in patients with AML rely heavily on ZMYND8 and thanks to a sophisticated CRISPR-based screening approach, we pinpointed the exact ‘druggable pocket’ to target,” commented senior author Junwei Shi.

“The findings suggest that delivering drug inhibitors against ZMYND8 could disrupt the AML vulnerable gene regulation circuits,” added Zhendong Cao, a PhD student investigator in Shi’s lab. “It is an opportunity to develop better precision medicine compounds than current treatments to treat this blood cancer – which we are currently working on right now.”

The researchers also found a biomarker – the expression level or the epigenetic status of the gene IRF8 from AML cells – to predict the sensitivity of cancer cells to a ZMYND8 inhibitor. Furthermore, the researchers validated the high expression of IRF8 and presence of IRF8 enhancer DNA element using blood samples from patients the University of Pennsylvania Medical School to support their finding.

“Many genetic and epigenetic alterations have been identified in cancer but few are actionable targets,” explained co-author Professor Shelley Berger. “CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on and one that we can potentially manipulate. It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.”

The study was published in Molecular Cell.

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