Study of tyrosine kinase inhibitors as preventive therapy in RUNX1-FPD

Abstract Familial platelet disorder (FPD) is a rare, inherited, dominant disease that is associated with high lifetime-risk of developing hematologic malignancies. FPD patients can live for decades in a “pre-leukemic” period before disease onset, opening a therapeutic opportunity for the development of preventive treatments. Molecularly, FPD is caused by germline mutations in the RUNX1 gene that reduce RUNX1 function, and is associated with clonal hematopoiesis and deregulated cytokine production in the immune system. Our preliminary results show that germline Runx1 mutations in mice create a pre-leukemic bone marrow niche marked by increased inflammatory cytokines, reduced DNA damage repair (DDR) response, and predisposition to hematologic malignancies. Furthermore, we found that treatment with the tyrosine kinase imatinib restored DDR response in vitro. Based on these preliminary data, we hypothesize that RUNX1 mutations hamper DDR response in hematopoietic stem and progenitor cells thereby promoting clonal hematopoiesis and the risk to developing hematologic malignancies. Furthermore, we propose that treatment with the tyrosine kinase inhibitor imatinib reduces clonal selection and may prevent disease onset by restoring DDR response. This hypothesis will be tested in the following three Specific Aims: 1. Determine the efficacy of the tyrosine kinase imatinib in restoring DDR response in human FPD pre-malignant cells. 2. Identify and characterize the pathways targeted by imatinib treatment in DDR of RUNX1-mutant hematopoietic cells. 3. Study the efficacy of tyrosine kinase inhibitors in preventing FPD-associated hematologic malignancies in mice. Together, these studies will provide mechanistic and functional insights into the role of RUNX1 mutations in DDR pathways, clonal selection and predisposition to hematologic malignances. Furthermore, they will establish whether treatment with tyrosine kinase inhibitors can reduce clonal selection and delay the onset of hematologic malignancies. These results may have a direct impact on the initiation of a phase-II clinical trial for FPD patients.