Researchers have developed a mouse model of an aggressive type of acute myeloid leukemia (AML) that, they believe, accurately replicates the human form of the disease.
The model replicates AML with co-occurring mutations in FLT3 and DNMT3A.
The researchers said they found that mice with Flt3-ITD and inducible deletion of Dnmt3a developed a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype.
The team described this work in Cancer Discovery.
“Our goal was to create a model that was faithful to the human form of the disease that can be used for preclinical testing of potential cures,” said study author H. Leighton Grimes, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Previous models were slow, difficult to analyze, and did not accurately represent the human disease. This model is rapid, fully penetrant, and completely spontaneous. We hope that it will open the way for other researchers to join us in attacking this particularly lethal AML subtype.”
Dr Grimes and his colleagues said they were able to look at the disease in a new way with the help of a powerful new core facility utilizing analytical tools related to single-cell RNA sequencing. The team used complementary single-cell analyses to identify the core leukemia-causing stem cells of the tumor.
“Before, researchers were comparing the gene expression patterns of one AML subtype to either normal cells or other AML subtypes,” said study author Sara Meyer, PhD, a fellow in the Grimes lab.
“That approach made it difficult to tease out the specific impact of Dnmt3a mutation. Instead, we isolated the variables and studied only human and murine AML with Flt3 mutation. Comparing Flt3-mutant AML with and without Dnmt3a mutation allowed us to more finely identify those patterns that were specific to the Dnmt3a mutation.”
With that more detailed understanding, the researchers gained new insights into the contributions of the Dnmt3a mutation to the disease.
First, their work confirms suspicions that low-level Dnmt3a activity is cancer-causing. Moreover, they discovered that reduced Dnmt3a function allows genes that are normally expressed only at early development stages of blood cell formation to continue expression at later stages, leading to the development of AML.
The researchers also found that, in mouse tumor cells, rescuing expression of Dnmt3a reversed the leukemia phenotypes and gene expression. But they said more research is warranted to determine if rescuing normal levels of DNMT3A function is a viable method for treating human AML.
The team also identified several potential treatment targets that are unique to this type of AML. In future studies, they plan to proceed with testing potential therapies.
