When a dangerous defect on chromosome 11q23 disrupts the genetic programming of blood cells, it causes an aggressive and deadly blood cancer called acute myeloid leukemia (AML). With a dismal survival rate of 20%-40% percent and desperate need for better treatments, scientists at Cincinnati Children’s report finding a potential therapeutic target for AML in pre-clinical laboratory tests on donated human cells and mice.

When scientists blocked the target molecule on human AML cells in combination with other known AML treatments, the cancerous blood cells died and were replaced by regenerating, healthy white blood cells, according to principal investigator H. Leighton Grimes, PhD, and study first author Sara Meyer, PhD, a former member of the Grimes laboratory.

The target molecule is F-box protein S-phase kinase-associated protein 2 (Skp2). Skp2 degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

Published online in the Journal of Experimental Medicine, the study’s findings are not ready for clinical application, according to Grimes. They do suggest the possible development of effective targeted therapies for AML.

“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,’’ said Grimes, director of the Cancer Pathology Program at Cincinnati Children’s. “We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if this approach will translate to patient care.”

Dangerous pairs

Abnormalities on 11q23 cause the fusion of harmful genes in aggressive AML blood cancer—the mixed-lineage leukemia (MLL) gene and a multitude of other genetic partners. In this study, the investigators closely analyzed MLL-AF9, which includes the AF9 gene, a frequent partner in AML.

One reason AML is so hard to treat is it aggressively re-emerges after initial therapy, which appears at first to diminish the disease in blood cells. But AML is refueled by so-called leukemia stem cells (LSCs)—precancerous blood cells that wait in the wings to evade treatment before launching a full-blown recurrence of disease.

Researchers report they were able to identify and disable the genetic and molecular programming that transform LSCs into AML. But getting to this point required extensive molecular detective work.