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.
Project Update 2024:
Children with FPD have a series of blood and immune complications during their lifetime, and have a high risk of blood cancers. These health problems are created by an inherited mutation in the RUNX1 gene. However, we do not understand how this mutation increases the risk to blood cancers. In order to understand the molecular changes created by mutations in RUNX1 on blood cell function and cancer, we set out to study how blood cell differentiation is affected and the predisposition to cancer increased, utilizing a mouse strain that carries germline mutation that mimics a Runx1 mutation found in FPD patients. We have completed the characterization of blood cell differentiation in these mice, and found that these mice can succumb to blood cancers overtime. We are now setting out to shed light on the factors, either environmental or from the blood stem cells, that predispose to blood cancers in patients with FPD.
