Study: New Target for Treating Chronic Myeloid Leukemia Found

Chronic myeloid leukemia (CML) is a type of cancer that has remained incredibly difficult to treat over the years. The National Cancer Institute estimates that 1.5% of men and women will be diagnosed with leukemia in their lifetimes, showing the necessity to discover successful treatments. Currently, although CML can be managed with targeted therapies, it becomes lethal if it advances or is diagnosed in an acute “blast” phase.²

Using CRISPR technology, researchers at University of California San Diego School of Medicine and Moores Cancer Center conducted a study aimed at identifying genes that fuel leukemia growth, in order to find new vulnerabilities that can be targeted.¹

The study successfully conducted screenings with genome-wide CRISPR technology by using primary cancer cells in the setting of the native microenvironment, said senior author Tannishtha Reya, PhD, professor in the departments of Pharmacology and Medicine, in a press release.²

Published on April 20, 2020 in Nature Cancer, the results of the study identified RNA-binding proteins as a key to sustaining and protecting drug-resistant leukemia stem cells. These RNA-binding proteins normally control how, when, and if cells make certain proteins, so the researchers decided to look at the relatively understudied member of the RNA-binding protein family called Staufen2 (Stau2). Stau2 was previously only understood to control brain and nervous system development.¹

Using a mouse model, the researchers genetically deleted Stau2 and discovered that the loss of this protein from the model led to a significant reduction in leukemia growth and propagation, as well as improved the overall survival rate. Stau2 was also found to be necessary to sustain the growth of primary tissue samples from patients with leukemia, which indicated to the researchers a conserved dependence in the human disease.¹

“We are particularly excited about this work because, to our knowledge, this is the first demonstration that Stau2 is a key dependency in any cancer,” said Reya, in a press release.²

In order to investigate how Stau2 is able to control cancer cells, researchers used a genome-scale computational analysis of its targets through RNA-Seq and eCLIP-Seq. The results led the researchers to the understanding that this protein controls key oncogenes, such as Ras, and epigenetic regulators, such as the LSD/KDM family of proteins, which are all targets that are currently being tested against leukemia and other cancers.¹

“This work will be particularly important for the discovery of new treatments,” said lead author Jeevisha Bajaj, PhD, a postdoctoral fellow at UC San Diego School of Medicine, in a prepared statement. “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.”²

REFERENCES

• Bajaj J, Hamilton M, Shima Y, et al. An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia. Nature Cancer. 2020. doi: 10.1038/s43018-020-0054-2.
• Finding leukemia's weakness using genome-wide CRISPR technology [news release]. ScienceDaily; April 20, 2020. sciencedaily.com/releases/2020/04/200420125543.htm. Accessed on April 22, 2020.