Linde Miles, PhD
Assistant Professor
Cincinnati Children's Hospital Medical Center
Research project
Interrogating oncogenic dependency in NPM1-mutant AML
Summary
Acute myeloid leukemia (AML) is a diverse set of blood malignancies that ultimately leads to a build-up of immature blood cells at the expense of mature functioning blood cells. The NPM1 gene is mutated in 20-35% of AML and defines a specific subset of AML patients. However, it is unclear exactly how mutant NPM1 (NPM1c) drives leukemia development and whether the imparted changes that occur within cells due to NPM1 mutations are reversible and/or crucial for cell survival. Moreover, it is not understood how co-mutations affect a cell’s dependency on mutant NPM1c protein. Recently, inhibitors of a protein complex, menin/MLL, have been shown to be effective in NPM1-mutant AML patients, but the totality of the connection between the inhibition of menin and inhibition of all Npm1c-dependent programs remains unexplored. Using a novel mouse model of mutant Npm1c, this proposal aims to define the cellular consequences of Npm1c mutation and whether loss or inhibition of Npm1c affects these atypical changes. These studies will improve the understanding of NPM1-mutant AML and has the potential to uncover novel therapeutic targets for AML patients harboring an NPM1c mutation.
Impact
The Leukemia Research Foundation grant was one of the first awarded to my independent lab, which holds a significant impact for me and our research. It provided critical support of a fledgling project that has become a central focus on my lab. Using the data generated from this project, we have also garnered enough preliminary data to submit an application for a multi-year federal grant. Continued funding for this project is absolutely critical for our research and our lab.
The findings from this project emphasizes how common co-occurring AML mutations can affect multiple variables of disease, including a cell’s dependency on specific oncogenes as well as potentially the cell’s response to new targeted therapies. Our studies have widespread implications that certain combinations of AML co-mutations have divergent vulnerabilities and may require unique therapeutic targets for effective treatment. Given the high prevalence of NPM1 mutations in AML (~30%), our studies have the potential to nominate novel therapeutic targets that may be highly effective in certain NPM1-mutant AML patient subsets and provide improved resolution to heterogeneity observed in NPM1 mutant AML patients. Moreover, our findings on menin inhibitor response could have future implications in altering clinical practice and treatment decisions based on the co-mutations present in NPM1c-mutant AML patients.
Leukemia Research Foundation grant
$150K awarded in 2023
Disease focus
Acute myeloid leukemia (AML)
Research focus
Cell Biology