A tool that was developed to study nerve cells in flies has been repurposed to study proteins in the blood of mammals that bind to the RNA in the process of protein synthesis. When genes are activated, messenger RNA transmits the protein synthesis instructions to the ribosomes that synthesize proteins. RNA binding proteins (RBPs) are essential to that process.
There are more than 1,500 RBPs in cells and each is critical for manufacturing proteins. Abnormalities in the activity of any one of those RBPs could contribute to a disease but studying individual RBPs is a challenge.
The tool – named HyperTRIBE – was repurposed by researchers at the Sloan Kettering Institute and has been used to study individual RBPs. The researchers have already used their tool to provide insights into an RBP involved in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a type of blood cancer characterized by abnormal myeloblasts, which produce white blood cells, red blood cells, and platelets. The researchers used their tool to study blood stem cells from mice and leukemia stem cells from mice and humans, specifically looking at an RBP called Musashi-2. This RBP is involved in the differentiation process of stem cells in the blood into other cell types and has previously been shown to be overactive in the cells of patients with AML.
“This is an exciting study because it changes how we study RBPs,” said Sloan Kettering Institute cancer biologist, Dr. Michael Kharas. “It also changes what we know about how they function in specific cells.”
Other methods have been developed for studying RBLs, but they cannot be used to study rare cells that are only available in very small numbers. HyperTRIBE uses a different approach, which allows those rare cells to be studied.
“Our study shows that this technique can be used to study RBPs, not just in fruit fly cells but more broadly,” said Dr. Kharas. “This will have global impact for anyone studying RBPs in rare cell populations, whether those are blood stem cells, neurons, germ cells, or other kinds of stem cells.”
Musashi-2 behaves differently in patients with AML than it does with regular blood stem cells. HyperTRIBE has already revealed new details about how Musashi-2 affects patients with AML.
“We knew that leukemia cells seemed to be more addicted to Musashi-2 for their growth than normal cells,” said Dr. Kharas. “Now we know that’s because Musashi-2 increases its RNA-binding activity and changes how RNA gets translated into proteins in cancer cells compared to normal cells.”
The researchers are now searching for molecules that can block the activity of Musashi-2 and could be used as new drugs to treat AML; however, considerable research needs to be conducted on how the drugs block the activity of Musashi-2 to ensure that any changes made would not affect the production of healthy cells.
Fortunately, since HyperTRIBE can be used to study RBPs in very small numbers, it will allow the researchers to conduct experiments and test potential drugs under a wide range of different conditions, which would not have been possible using current methods for studying RBPs.
You can read more about the study in the paper –HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells – which was recently published in the journal. DOI: 10.1038/s41467-020-15814-8