Stopping Leukemia in its Tracks
Researchers have discovered a way to block the activity of the cancerous cell that generates some forms of acute myeloid leukemia.
“It seems we have found the Achilles’ heel of this form of cancer,” said H. Leighton Grimes, PhD, of the Division of Immunobiology at Cincinnati Children’s. And it appears to be tiny bits of genetic material.
The discovery began last year when Grimes developed the first mouse model for a disease called severe congenital neutropenia. Twenty percent of patients with this disease also develop acute myeloid leukemia. Although past attempts to reproduce congenital neutropenia in mice had failed, Grimes’ lab was successful when they mutated a gene called GFI1. “GFI1 is like a light switch that turns off the expression of other genes,” Grimes says.
With this new GFI1-deficient mouse model, a pathway to acute myeloid leukemia unfolded. Grimes found that GFI1 normally blocked the signals from other pieces of genetic material, called microRNAs. In certain types of acute myeloid leukemia, cancer formation seemed to hinge on the messages that two specific microRNAs were sending. “GFI1 is actively fighting to suppress these microRNAs,” says Grimes. “If we over-express GFI1 in cancerous cells, it suppresses the microRNAs and the transformation [from regular cells to cancerous cells].”
Stopping the microRNAs stopped the cancer, says Grimes, even without forcing GFI1 expression. “In mouse models of leukemia, in which each in vitro colony has the capacity to initiate leukemia in a recipient, the number of colonies is dramatically lower by getting rid of these microRNAs,” he said. “The translation of that is, if you treat the kids with these small-molecule inhibitors, you could eradicate the disease.”
Unlike chemotherapy that targets both healthy and cancerous cells, causing a variety of side effects, the microRNA inhibitors have not caused problems in Grimes’ mice. Although he cautions that years of testing will be needed before the findings can be applied to clinical use, Grimes says the discovery could lead to better treatments with fewer side effects.
