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Identifying Key Regulating Proteins in CML With CRISPR Technology

By: Lauren Harrison, MS
Posted: Friday, June 12, 2020

The double-stranded RNA-binding protein Staufen2 was identified as a critical dependency of myeloid malignancies such as chronic myeloid leukemia (CML) through the use of CRISPR-Cas9 technology. Tannishtha Reya, PhD, of the University of California San Diego School of Medicine, and colleagues published their findings in Nature Cancer.

“CRISPR is an extremely powerful tool that allowed us to identify a multitude of genes that fuel leukemia growth and find new vulnerabilities that can be targeted in this disease,” said Dr. Reya in a UC San Diego Health press release. “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.”

Researchers performed a genome-wide in vivo CRISPR screen in leukemic stem cells to identify Staufen2 as a key protein in disease growth. Expression of the BCR-ABL oncogene led to a 1.2-fold increase in Staufen2 expression, whereas a combination of BCR-ABL and NUP98-HOXA9 expression (as seen in blast crisis CML) enhanced the expression of Staufen2 by fourfold in CML stem cells. Administration of a BCR-ABL kinase inhibitor reduced Staufen2 expression in these cells.

Using this knowledge, they injected mice with both wild-type and knockdown Staufen2 leukemic stem cells. Although none of the control mice survived, approximately 60% of the Staufen2-knockdown mice survived. In addition, when mice were bred with a deletion of Staufen2, there was a twofold reduction in the establishment of CML compared with wild-type mice. Staufen2 was found to be required for development of primary blast crisis in CML.

Researchers used a combination of CRISPR, RNA sequencing, and high-throughput sequencing to establish the molecular effectors that mediate the impact of Staufen2. Their data suggest this protein may be a regulator of chromatin binding factors and may drive global alterations in histone methylation.

Disclosure: For a full list of author disclosures, visit www.nature.com.



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