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crispr screening

PHILADELPHIA—A CRISPR screening tool identified a new therapeutic target to treat acute myeloid leukemia (AML) that has the potential to leave patients with fewer side effects than current approaches, according to a new study from Penn Medicine published online in Molecular Cell. The target, known as ZMYND8, isn’t a mutated gene, rather an epigenetic regulatory protein that cancer cells need to control gene expression crucial for them to stay alive and grow.

“We’ve 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,” said senior author Junwei Shi, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania, and member of the Penn Epigenetics Institute and Abramson Family Cancer Research Institute.

“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’s an opportunity to develop better precision medicine compounds than current treatments to treat this blood cancer—which we are currently working on right now.”

AML affects more than 20,000 patients a year, including both children and adults, and has a five-year survival rate of just 27 percent for people over 20. The standard of care includes chemotherapy; however, not all patients respond, so newer approaches are needed to expand options and improve survival.

CRISPR has allowed scientists to not only modify genes with more ease and less cost than previous approaches, but also enabled them to simultaneously screen for thousands of specific functional protein domains with high potential for therapeutic targeting.

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 ZMYND8 in mice left them with smaller tumors and better survival.

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 treated at Penn Medicine to support their finding.

“Many genetic and epigenetic alterations have been identified in cancer but few are actionable targets,” said co-author Shelley L. Berger, PhD, the Daniel S. Och University Professor in the departments of Cell and Developmental Biology and Genetics in the Perelman School of Medicine and director of the Penn Epigenetics Institute. “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 supported with a Linda Pechenik Montague Investigator Award, by the Cold Spring Harbor Laboratory sponsored research, and start-up package from University of Pennsylvania.


Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $496 million awarded in the 2020 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 44,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2020, Penn Medicine provided more than $563 million to benefit our community.

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