Johns Hopkins Kimmel Cancer Center investigators have genetically engineered a new mouse that mimics a common form of leukemia in humans. Studying the model could lead to new understanding of the disease, they say.
The mice were bred to express a protein mutation within a gene known as FMS-like tyrosine kinase 3 (FLT3). The gene that forms FLT3’s blueprint controls the development of healthy blood cells; mutations to it are seen in approximately a third of adult and pediatric cases of acute myeloid leukemia (AML).
Mutations in FLT3 are found in various regions of the gene, and the Hopkins scientists designed the mouse to better understand the workings of the two most common ones in AML. They are: ITD mutations, which cause a very aggressive form of the disease, and D835Y mutations, which cause a less aggressive form of the disease. The new mouse specifically expresses D835Y mutations. Mice bred to express ITD mutations were previously developed by the Hopkins team.
To date, scientists have not understood why the ITD mutations cause more aggressive disease, says Donald Small, M.D., Ph.D., the Kyle Haydock Professor of Oncology and director of pediatric oncology at Johns Hopkins. Small led a team of researchers who originally cloned the FLT3 gene and linked it to leukemia a decade ago.
Patients with ITD mutations have only a 15 percent chance of a cure, Small says, compared with patients who have D835Y mutations, who have about a 50 percent chance of a cure. Studies comparing the new mice, containing D835Y mutations, with mice expressing ITD mutations provide “an ideal platform for dissecting the molecular mechanisms underlying the differences between the two mutations, and for drug screening against the two,” he says.