Individuals with RUNX1 familial platelet disorder (RUNX1-FDP) have a high risk of developing aggressive bone marrow disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, no current interventions can effectively prevent progression to AML in patients with RUNX1-FPD. Thus, it is critical to understand the biological mechanisms causing the development of these diseases in RUNX1-FDP individuals and to develop novel therapies that can prevent progression. Recent studies suggest that RUNX1 mutations lead to upregulation of inflammatory gene signatures in hematopoietic stem and progenitor cells (HSPCs), resulting in hypersensitivity to certain inflammatory stimuli, which may promote the growth and progression of RUNX1-mutant cells. Additionally, development of MDS and AML in RUNX1-FPD individuals is associated with the acquisition of mutations in additional genes, which may further increase the response of HSPCs to inflammatory signaling. These findings suggest that targeting inflammation may be a potential treatment strategy in preventing progressing to MDS or AML for individuals with RUNX1-FDP.
Ravi Majeti and his collaborators are using computational tools and experimental methods to identify existing drugs that can be repurposed to target inflammation in RUNX1-FPD, and to model the effect of additional acquired mutations on inflammation and progression of RUNX1 FPD to AML. By combining computational tools, primary cell models, and patient data, they will develop a deeper understanding of how a combination of inflammation and acquired mutations contribute to the pathogenesis of myeloid malignancy, and other inflammatory conditions such as autoimmune disease or allergy, in RUNX1-FPD patients. Importantly, these studies will also identify and provide pre-clinical validation of pharmacologic agents, many of which may already be approved for other indications, that may be repurposed to ameliorate, delay, or prevent disease progression in RUNX1-FPD patients.