National Cancer Institute 5U01CA296350-02

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

This NIH-funded project studies the use of tyrosine kinase inhibitors, specifically imatinib, as preventive therapy for familial platelet disorder caused by RUNX1 mutations, aiming to restore DNA damage repair and reduce malignancy risk.

Description

Familial platelet disorder (FPD) is a rare, inherited, dominant disease associated with high lifetime risk of developing hematologic malignancies. FPD is caused by germline mutations in the RUNX1 gene, leading to reduced RUNX1 function, clonal hematopoiesis, and deregulated cytokine production. Preliminary studies in mice show that germline Runx1 mutations create a pre-leukemic bone marrow niche with increased inflammatory cytokines and reduced DNA damage repair (DDR). Treatment with the tyrosine kinase inhibitor imatinib restored DDR response in vitro. The project hypothesizes that RUNX1 mutations impair DDR in hematopoietic stem and progenitor cells, promoting clonal hematopoiesis and malignancy risk, and that imatinib can reduce clonal selection and prevent disease onset.

View original record