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.
In work published online Nov. 18 in the journal Proceedings of the National Academy of Sciences, Small and his colleagues reported that FLT3 mutation types (either D835Y or ITD) are directly related to the aggressiveness of disease. In laboratory studies, the investigators found that mice with D835Y mutations, like people, develop much less aggressive disease than those with ITD mutations, both in disease severity and survival. D835Y mice lived an average of 1.5 times longer than those with ITD mutations - an average of 678 days versus 430 days. Those with the D835Y mutations also maintained a higher white blood-cell count and were not nearly as depleted in blood stem cells as those with the ITD mutations. The D835Y mutant mice also developed a broader spectrum of blood cancers, including lymphomas.
Investigators also tested the anticancer drugs Lestaurtinib (CEP-701) and sorafenib in the two types of mice. After 48 hours of treatment, the FLT3/D835Y mice responded to Lestaurtinib only, while the FLT3/ITD mice responded to both drugs.
"This new mouse model should enable us to further explore why patients with FLT3/ITD mutations have worse prognosis," Small says. He and his team, he says, will be looking at the genes turned on and off by these mutations to further study molecular changes involved in leukemia development, and investigate pathways involved in other leukemias.
Coauthors of the study were Emily Bailey, Li Li, Amy S. Duffield, Hayley S. Ma, and David L. Huso. The work was supported by a National Institutes of Health (CA 090668 and CA 070970), the Leukemia & Lymphoma Society, and the Giant Food Pediatric Cancer Research Fund.
On the Web:
Link to the PNAS study:
Description of Dr. Small's work:
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