Hopkins scientists design new mouse that mimics common form of leukemia

NewsGuard 100/100 Score

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.

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.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Novel therapeutic approach identified for overcoming resistance in B-cell leukemia