Modeling familial platelet disorder associated RUNX1 mutations in mice
The molecular mechanisms responsible for the pathology of familial platelet disorder and predisposition to leukemia are poorly understood. This understanding is essential for the development of effective therapies that can preempt leukemia transformation. Fortunately, a number of approaches are being developed to study these mechanisms in cell base assays. However, there are no good animal models that mimic the disease mutations. We are developing mouse strains with four FPD-associated mutations in the Runx1 gene, mimicking mutations found in FPD patients. The studies proposed in this application will define the impact of FPD-associated Runx1 mutant alleles in disease presentation, sensitivity to micro-environmental stress, heterogeneity, and in leukemia progression in vivo. The mice generated by this project will provide the FPD/RUNX1 community with sophisticated FPD mouse models to expand future research in other areas, including the role of a mutated microenvironment in hematopoietic differentiation, DNA-repair dysfunction, and evaluation of somatic “cooperating” events in leukemia development. Finally, these mice will serve as valuable tools to test candidate drugs for FPD therapy.