Characterization of Pre-Leukemia Associated with Familial RUNX1 Mutations
Familial mutations in the RUNX1 gene result in an inherited disorder characterized by an increased risk of progression to acute myeloid leukemia (AML). RUNX1 encodes a factor critical for normal blood development and the mutations are thought to block its functions. Progression to AML requires additional mutations, indicating that the familial mutations establish a pre-leukemic state. Notably, RUNX1 is also expressed during bone development, raising the possibility that the disease and progression to AML are also promoted by an abnormal bone marrow environment.
Here, we propose to investigate disease development and pre-leukemia through two complementary aims. First, we will determine the effects of familial RUNX1 mutations on blood-forming stem and progenitor cells (HSPCs). Familial RUNX1 mutations will be engineered into HSPCs that will then be assayed for defects in HSPC functions. Second, we will determine the contributions of familial RUNX1 mutations in HSPCs and the bone marrow environment to abnormal blood development.
We have recently developed methods to establish a humanized bone marrow in mice that can then serve as a site for human blood growth and development. Using these methods, we will mutate RUNX1 in HSPCs, transplant them into the humanized bone marrow and assess for effects on blood development. In parallel, we will engineer RUNX1 mutations into the humanized bone marrow and assess for effects on blood production from normal HSPCs. Finally, we will examine the growth and development of blood from RUNX1-mutated HSPCs in the RUNX1-mutated bone marrow environment to identify combinatorial effects.