Scientists at the University of California San Diego School of Medicine report that high ADAR1 enzyme levels correlate with reduced survival rates among patients with multiple myeloma (MM). They also determined that blocking the enzyme reduces MM regeneration in experimental models derived from patient cancer cells.
The study (“Alu-Dependent RNA Editing of GLI1 Promotes Malignant Regeneration in Multiple Myeloma”), published in Nature Communications, also suggests that a class of commercially available drugs could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in MM.
“Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on RNA (ADAR)1 gene, occurs in 30–50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance,” write the investigators.
“Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set. Expression of wild-type, but not mutant, ADAR1 enhances Alu-dependent editing and transcriptional activity of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist, and promotes immunomodulatory drug resistance in vitro. Finally, ADAR1 knockdown reduces regeneration of high-risk MM in serially transplantable patient-derived xenografts. These data demonstrate that ADAR1 promotes malignant regeneration of MM and if selectively inhibited may obviate progression and relapse.”
“That's why it's exciting that this discovery may allow us to detect the disease earlier, and address the root cause,” said senior author Catriona Jamieson, M.D., Ph.D., professor of medicine, Koman Family Presidential Endowed Chair in Cancer Research and chief of the Division of Regenerative Medicine at UC San Diego School of Medicine.
ADAR1, which is normally expressed during fetal development to help blood cells form, edits the sequence of RNA. By swapping out just one RNA building block for another, ADAR1 alters the carefully orchestrated system cells use to control which genes are turned on or off at which times, noted Dr. Jamieson.
ADAR1 is known to promote cancer progression and resistance to therapy. In previous studies, Dr. Jamieson's team described ADAR1's contributions to leukemia. The enzyme's RNA-editing activity boosts cancer stem cells, giving rise to cancer, increasing recurrence, and allowing some cancers to resist treatment.
In analyzing a database of nearly 800 multiple myeloma patient samples for the current study, the team discovered that 162 patients with low ADAR1 levels in their tumor cells survived significantly longer over a three-year period compared to 159 patients with high ADAR1 levels. While more than 90% of patients with low ADAR1 levels survived longer than two years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels were alive after the same period of time.
To unravel exactly how ADAR1 is connected to disease severity at a molecular level, the researchers transferred MM patient tissue to mice, creating a xenograft.
“This is a difficult disease to model in animals—there isn't a single gene we can manipulate to mimic MM,” said co-senior author Leslie A. Crews, Ph.D., assistant professor at UC San Diego School of Medicine. “This study is important, in part because we now have a new xenograft model that will for the first time allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
Using their new model, Drs. Jamieson, Crews, and colleagues found that two events converge to activate ADAR1 in MM—a genetic abnormality and inflammatory cues from the surrounding bone marrow tissue. Together, these signals activate ADAR1, which edits specific RNA in a way that stabilizes a gene that can make cancer stem cells more aggressive.
They also found that silencing the ADAR1 gene in the xenograft model reduced MM regeneration. Five- to 10-fold fewer tumor cells were able to self-renew in mice lacking ADAR1, suggesting a new therapeutic target.
Clinical trials that specifically test ADAR1-targeted therapeutics for their safety and efficacy against MM are still necessary before this approach could become available to patients. To advance their initial findings, Drs. Jamieson and Crews are exploring ways to leverage ADAR1 to detect MM progression as early as possible. They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models. Several JAK2 inhibitors have already been approved by the FDA or are currently in clinical trials for the treatment of other cancers.
“Several major advances in recent years have been good news for MM patients, but those new drugs only target terminally differentiated cancer cells and thus can only reduce the bulk of the tumor,” said Dr. Jamieson, who is also deputy director of the Sanford Stem Cell Clinical Center, director of the CIRM Alpha Stem Cell Clinic at UC San Diego, and director of stem cell research at Moores Cancer Center at UC San Diego Health. “They don't get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach 'precision regenerative medicine.' “