Most studies on how multiple myeloma develops focus on DNA abnormalities, but new research has uncovered an association between abnormalities in RNA and the cancer’s progression.
Multiple myeloma is the second most common type of blood cancer where cancer cells accumulate in the bone marrow, crowding out healthy blood cells.
Researchers discovered that over-expression of ADAR1, a RNA-editing enzyme, and a modified gene that irregular RNA editing causes are key to multiple myeloma progression and the development of resistance to current treatments.
Survival rates for these patients have significantly improved over the years with several new drug discoveries for the disease. However, about 10 to 15 percent continue to be classified as high risk patients with low survival rates even when treated with the available drugs, as they develop resistance to treatments.
Previous research on multiple myeloma in the last decade has mostly been aimed at understanding how DNA abnormalities contribute to its development, but more recently, researchers have found that RNA abnormalities are associated with different cancers such as gastric cancer and liver cancer.
As such, the research team embarked on a study to investigate the biological implications of RNA defects on the progression of multiple myeloma to better understand how drug resistance develops in high risk patients.
The team’s analysis revealed that multiple myeloma RNA exists in an abnormally modified state, which consequently promotes the cancer’s progression in two ways.
The first is an abnormally elevated level of ADAR1 expression in myeloma cancer cells, which causes them to acquire stronger cancer properties.
The second is the irregular RNA editing of NEIL1, a gene associated with lung carcinoma and colorectal cancer. NEIL1-edited myeloma cancer cells demonstrate a more cancerous nature where they lose the ability to repair DNA damage and show increased resistance to a standard MM drug.
Researchers found that, collectively, patients with high ADAR1 expression and compromised NEIL1 function were less responsive towards the available treatments for the disease.
In light of this new understanding, researchers also identified a group of drugs, known as DSB-inducing agents, which can inhibit NEIL-edited cells, opening the door for new, effective treatment options for high risk MM patients.
“Our study has shown that RNA defects is both clinically and biologically relevant in MM, and by exploring these RNA abnormalities further, we may unravel more novel insights on MM molecular pathogenesis,” says lead study author Chng Wee Joo, deputy director and senior principal investigator at the Cancer Institute of Singapore at the National University of Singapore.
“Each piece of new knowledge derived will be key in helping to complete the puzzle of MM biology, paving the way for the development of innovative therapies that can curb drug resistance and raise the survival rates of high risk MM patients.”
The research appears in the journal Blood.
Source: National University of Singapore