Body’s RNA-editing system targeted to treat drug-resistant leukemia

University of California, San Diego researchers have identified the process by which the precancerous precursors of white blood cells become leukemia stem cells: the human body's own gene-editing process. Targeting an RNA-editing enzyme may lead to a new approach to treating blood cancers.

The team, led by senior author Dr. Catriona Jamieson, studied how cancer stem cells hijack the body’s RNA-editing system to clone themselves. In particular, they examined ADAR1, which is known to drive cancer progression and drug resistance. They used human blast crisis chronic myeloid leukemia cells in the lab, as well as cells transplanted into mice, to identify ADAR1’s role in governing leukemia stem cells, the team said in a statement. Blast crisis is an aggressive, therapy-resistant form of leukemia.

They found that white blood cells with a gene mutation that promoted leukemia were more sensitive to signs of inflammation, launching a response that activated ADAR1. “Hyper-ADAR1 editing” then stalled microRNAs called let-7, which promoted cellular regeneration, or self-renewal, turning white blood cell precursors into leukemia stem cells.

By treating blast crisis myeloid leukemia cells with a small molecule called 8-Aza, the researchers cut their self-renewal by about 40%, as compared to the untreated cells.

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. 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,” Jamieson said in the statement.

A number of studies have focused on the role of DNA mutations in cancer, but the role of RNA and the mechanisms that regulate it are gaining traction. In January this year, Cold Spring Harbor scientists removed Malat1, a long noncoding RNA, from mouse models and found that aggressive cancer cells were less likely to spread. And in March, an Imperial College team discovered a microRNA, miR-515-5p that could target the aggressive metastasis of breast and lung cancers.

- read the statement
- here's the study abstract

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