Led by associate professor of medicine Catriona Jamieson, M.D., Ph.D., the team published their findings in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences. The team identified a crucial enzyme in the reprogramming process that causes stem cells to grow malignantly, causing chronic myeloid leukemia, or CML.
CML is a slow-growing cancer caused by the mutant gene called BCR-ABl. The gene in the blood forms stem cells that lead to an explosion of white blood cells. With a median diagnosis age of 66, the disease becomes more common with age and is often not diagnosed until its later stages. An estimated 70,000 people in the United States have the disease, with the number projected to more than double to 181,000 by 2050. Scientists have yet to pinpoint the reason for the mutation.
CML, a type of cancer of the blood and marrow, is becoming more widespread despite the arrival of new therapies, such as tyrosine kinase inhibitors, a drug that prevents cancerous cells from regrowing by inhibiting the tyrosine kinase enzyme.
In the paper, Jamieson and her colleagues in the United States, Canada and Italy reported that inflammations caused by microbial infections boosts activity of an enzyme called adenosine deaminase, or ADAR1. Long-term inflammation is known to be associated with the development of cancer due to the body’s natural process of getting rid of harmful microbes.
The team found that the effect of ADAR1 caused the RNA to combine incorrectly, or mis-splice, leading to greater self-renewal and therapeutic resistance of malignant stem cells. The findings expand upon previous studies by Jamieson and others that explain the effects of RNA mis-splicing and instability.
“People normally think about DNA instability in cancer, but in this case, it’s how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy,” Jamieson said in a Jan. 2 press release by UCSD.
The researchers’ findings showed that inflammation is a key part of cancer relapse and failure of therapeutic treatments. It is now being targeted for new therapies in the future.
Jamieson explained that researchers may be able to inhibit ADAR1 with a small molecule inhibitor, a method already successfully implemented with other inhibitors. An inhibitor is a drug that prevents the growth of certain cells at the molecular level by restricting their access to enzymes that expedite growth. Blocking leukemia stem cells’ access from ADAR1 creates the possibility of preventing malignant cell cloning.
