CRISPR Helps Unearth Novel drug Target for Leukemia

By Sahana Shankar, Ph.D. candidate

Scientists from UCSD identify key regulators of aggressive, chronic myeloid leukemia via a genome-wide CRISPR screen.

Leukemias are one of the most aggressive cancers which affect both adults and children with poor prognosis and survival rates. In a new study, published in Nature Cancer, investigators from the University of California, San Diego School of Medicine report a new strategy to combat it. They employ the CRISPR-Cas9 technology to identify novel regulators of blood cancers, specifically chronic myeloid leukemia (CML) that is difficult to treat in advanced stages.

Since its arrival, CRISPR has facilitated DNA manipulation with unprecedented precision and accuracy, a capability that has been regarded as the holy grail of medicine and biological research for long. This study once again demonstrates that CRISPR is an effective tool to perform in vivo genetic screens.

RNA-binding proteins (RBPs) are essential to maintaining cells as they sustain cell proliferation, post-transcriptional regulation, and other aspects of cell behavior. They bind to specific RNA sequences to drive mRNA translation, stability, transport, and localization. Many RBPs are known to be misregulated in cancers and contribute to tumor development.

Using primary cancer cells, the authors blocked a wide spectrum of genes using CRISPR-Cas9 to identify potential therapeutic targets that promote cancer growth. According to lead author, Dr. Tannishtha Reya, “the study also shows, for the first time, that whole genome CRISPR-based screens can, in fact, be carried out in a manner that is much more physiologically relevant: using primary cancer cells and in the setting of the native microenvironment.” From the genome-wide study, the team discovered 6 RBPs to be abundantly expressed in leukemia stem cells and critical regulators of myeloid leukemia.

They performed a proof-of-study by characterizing the double stranded RBP Staufen 2 (Stau2) as a driver of leukemia stem cell proliferation and drug resistance. Stau2 was previously a known regulator of the brain and nervous system development. To validate their findings, the team developed a Stau2 knockout mouse model to understand its role in cancer regulation and demonstrated a significant decrease in leukemia cell growth, proliferation, and an increase in overall survival. Primary tissue from leukemia patients also required Stau2 for continued growth, suggesting a conserved function for Stau2 in tumor development and progression.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration that Staufen2 is a key dependency in any cancer,” said Reya, who is a member of Moores Cancer Center and the Sanford Consortium for Regenerative Medicine.

To understand the molecular details of how Stau2 is important in tumor cell proliferation, the researchers looked at its binding partners and interactors by RNA-Seq and eCLIP-seq and found that Stau2 regulates important oncogenes (Ras), epigenetic factors and chromatin remodellers such as histone demethylases. Most of these are potential drug targets and hence any information on their regulation helps design better therapies.

“This work will be particularly important for the discovery of new treatments. Our genome-wide screen identified cellular signals critical for the growth of cancer, and in the future, this study will be useful to study the microenvironment, the area around the tumor that includes tissue, blood vessels and important molecular signals related to how the cancer behaves,” first author, Dr.Jeevesha Bajaj sums up the study.

Related Article: Evolved Cas9 Facilitates CRISPR Access to Previously Unexplored Genomic Sites

References

1. https://www.nature.com/articles/s43018-020-0054-2#article-info
2. https://ucsdnews.ucsd.edu/pressrelease/finding-leukemias-weakness-using-genome-wide-crispr-technology
3. https://www.urmc.rochester.edu/news/story/5642/researchers-find-new-leukemia-genes-using-crispr-technology.aspx

Author

Sahana Shankar