Chronic myeloid leukemia blood cells
Researchers led by a team at the University of California, San Diego, School of Medicine have determined that overexpression of the ADAR1 enzyme, which is responsible for RNA editing, ramps up cellular regeneration, causing white blood cell precursors to develop into leukemia stem cells. Even more significantly, the investigators determined that a small-molecule tool could counteract the overexpression of ADAR1 and reduce the regeneration of leukemia cells.
The study was published Thursday on the website of the journal Cell Stem Cell.
“We showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down,” principal investigator Dr. Catriona Jamieson said in a news release. Jamieson is chief of regenerative medicine at UCSD.
To conduct the experiment, the team of 20 researchers transplanted human blast crisis chronic myeloid leukemia cells into mice. Using this mouse model, they found that white blood cells with a genetic mutation associated with leukemia were more sensitive to inflammatory signals. The inflammation in turn unleashed the ADAR1 enzyme governing RNA editing.
The RNA editing by the ADAR1 enzyme subsequently slowed microRNA molecules known as let-7, which have been shown to inhibit the growth of tumor cells. The research team then determined that dampening the expression of ADAR1 using a small-molecule tool called 8-Aza significantly reduced the regeneration of the blast crisis chronic myeloid leukemia cells by 40 percent when compared with control cells.
Jamieson said that assessing ADAR1 expression will be a useful tool for predicting cancer progression.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
“In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed,” she said.
Dr. Karim Mekhail, an associate professor of laboratory medicine and pathobiology at the University of Toronto, who researches RNA and human disease, commented that the study provides insights regarding the interplay between RNA and cancer development.
“Our genetic information flows from DNA to RNA to protein,” Mekhail said. “While we commonly associate human diseases including cancer to mutations in DNA, we now also appreciate that cancer is driven in large part by RNA molecules and the processes controlling them. This study is very important as it identifies how the RNA editing function of ADAR1 contributes to a particularly aggressive form of cancer while opening the door to new prognostic and therapeutic avenues.”
Photo: UC San Diego Health
