Targeting MicroRNA Emerges As Potential Weapon Against Acute Myelogenous Leukemia
When acute myelogenous leukemia (AML) strikes, five-year survival rates vary dramatically (15 percent–70 percent) depending upon the AML subtype. Children diagnosed with AMLs with 11q23 translocations have experienced especially poor outcomes.
However, a new approach based on silencing targeted microRNAs that was developed by a Cincinnati Children’s research team led by H. Leighton Grimes, PhD, has shown intriguing early success in mouse models. MicroRNAs have long been thought to play an important role in oncogenesis, but so far, converting this concept into therapeutics has been slow. Grimes and colleagues found one potential solution by exploiting an ancient competition between GFI1 and HOX transcription factors, which both act as leukemia-initiating “gatekeeper” pathways.
As the team studied the competing transcription factors, they found two microRNA that appeared to play important roles in AML relapse. The team went on to test antagomir treatment as a tool to silence the targeted microRNA.
“Therapeutic inhibition of microRNA-21 and microRNA-196b inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models,” Grimes and co-authors wrote.
The study establishes microRNA as functional effectors of endogenous HOXA9 and HOX-based leukemia oncoproteins. At one level, this means the research world now has a mouse model that can serve effectively as an in vivo platform to test RNA-based cancer therapies. At another level, it means children who develop notoriously hard-to-treat forms of AML may have increased hope for longer-term survival.
“Overall, our studies provide a strong rationale to develop microRNA antagonists for clinical use in AML,” Grimes says.
