Published August 2018 | Journal of Experimental Medicine
Cancer experts have learned over the years that especially aggressive forms of acute myeloid leukemia (AML) feature harmful fusions between the mixed lineage leukemia gene (MLL) and various other cancer-promoting genes. These fusion genes often help leukemia stem cells evade initial chemotherapy and fuel rapid, often-fatal relapse.
Previously, the lab of H. Leighton Grimes, PhD, showed that targeting microRNA could block the leukemia stem cell of AML cancers featuring the fusion gene MLL-AF9 to cure a model of the disease. In this study, Grimes and first author Sara Meyer, PhD, led a team that closely analyzed MLL-AF9-induced AML by “fishing” with a microRNA miR-196 bait to identify the targets of miR196 within the AML cells. Next, they used an in vivo screen to figure out which targets were most important for the aggressive behavior of MLL-AF9-induced leukemia.
Further study revealed that miR-196 inhibits the gene Cdkn1b (encoding the cell cycle regulator p27Kip1) to support leukemia stem cell survival and spread. The level of p27 protein functions as a lever to control AML stem cell activity. To validate p27 as a target in AML, the team used an experimental small molecule called SLZ P1041, which inhibits Skp2; a protein that orthogonally regulates p27 levels. Toggling p27 through Skp2 inhibition in mice resulted in cancer cell death and replacement with healthy white blood cells.
“Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets. It serves as an example of moving between oncogenic microRNA to clinically tractable targets for AML therapy,” Grimes says.
The team predicts that SLZ P1041 will work best in combination with other small-molecule inhibitors. So far, the most intriguing combination involves SLZ P1041 and Ml-1, which inhibits interactions between Menin and MLL proteins.