Gene Expression Modification Shows Promise as Leukemia Treatment

Errors in regulating gene expression could promote the development of acute myeloid leukemia (AML), according to a new study published by Nature Medicine. AML is a common type of blood cancer that is notoriously difficult to treat.

The authors found that patients with AML had high expression of an enzyme that places chemical marks (methyl groups) on messenger RNA (mRNA). By reducing the levels of the enzyme, AML cells were observed to behave normally.

The authors suggest that these findings may result in novel treatments for AML that regulate mRNA, according to the study.

“This is a totally new way of thinking about how cancer may be regulated,” said researcher Michael Kharas, PhD.

Researchers have hypothesized that gene expression changes can increase the risk for certain types of cancer and have searched for a way to regulate DNA to reverse the alterations. The authors of the current study focused on how methyl groups on mRNA can alter gene expression.

The mRNA work as a messenger between DNA and the cell’s protein-building machinery. Methyl groups added to mRNA can control which genetic information is turned into proteins, according to the authors.

Normally, genes either encourage cells to become cancerous or suppress tumors; however, if the balance is disrupted, cancer can develop, according to the study.

“If the methyl groups are not properly placed, the balance of tumor facilitators and tumor suppressors can go wrong,” said researcher Samie Jaffrey, MD, PhD.

In the study, the authors discovered that patients with AML have high expression of the METTL3 enzyme, which places methyl groups on RNA.

When METTL3 was reduced in human cells, fewer methyl groups were placed on RNA. Notably, cancer cells began behaving as normal cells and then died, according to the study.

“Suddenly, they don’t look like cancer cells under the microscope, and they differentiate in the types of cells they are supposed to be,” Dr Jaffrey said. “This is very important because this is one of the major goals in leukemia treatment, to cause cancer cells to differentiate into normal-behaving cells.”

In patients with leukemia, cells are unable to mature into necessary immune cells. Restoring the normal life and death cell cycle is crucial to cancer recovery, according to the authors.

The authors also found that when mice were injected with leukemia cells with lowered METTL3 levels, cancer development was slowed.

The researchers are now searching for drugs that bind to METTL3 or other proteins that could induce remission in animal models. If successful, the authors project that targeting abnormal mRNA methylation could be a novel way to fight cancer.

Despite the positive findings, the authors warn that additional testing is necessary to ensure that any potential treatments do not affect healthy cells, according to the study.

“It’s clearly the early days of understanding this RNA pathway and whether it might be a therapeutic target,” Dr Kharas said.