Fighting Acute Myeloid Leukemia
By targeting a couple of small, key pieces of genetic material, researchers have discovered a way to block the activity of the cancerous cell that generates some forms of acute myeloid leukemia. This could lead to better treatments that have fewer side effects. “It seems we have found the Achilles’ heel of this form of cancer,” said H. Leighton Grimes, PhD, who works in the Division of Immunobiology at Cincinnati Children’s. “We were very surprised that by targeting these very small things, we could halt the leukemia.”
The discovery began in a roundabout way. Last year, Grimes developed the first mouse model for a disease called severe congenital neutropenia. A curious aspect of the disease is that 20 percent of patients also develop acute myeloid leukemia. Although attempts to reproduce the disease in mice had failed in the past, Grimes’s lab was successful when they mutated a gene called GFI1. “GFI1 represses other genes, so it’s like a light switch and it turns off the expression of the other genes,” he said.
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,” said Grimes. “If we over-express GFI1 in cancerous cells, it suppresses the microRNAs and it suppresses transformation [from regular cells to cancerous cells].”
Even better, stopping the microRNAs stopped the cancer, even without forcing GFI1 expression. “We’ve developed small-molecule inhibitors of these microRNAs. What’s really interesting is that 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. “And the translation of that is if you treat the kids with these small-molecule inhibitors, you could eradicate the disease.”
Chemotherapy today targets both healthy and cancerous cells, causing a variety of side effects. But Grimes’s mice have not shown side effects from the microRNA inhibitors. “Taking our findings from the laboratory to the clinic will require years of testing,” said Grimes. “But we are excited by the prospect directly targeting the cancer in patients.”
