Mutations in the TET2 gene can be the “first–event” in the transformation of hematopoietic stem and progenitor cells (HSPCs). When HSPCs in the bone marrow lose the function of TET2, they become more competitive and expand at the expense of the normal HSPCs, and then accumulate mutations in other genes, leading to the onset of Myelodysplastic Syndrome (MDS). In human patients, this pre-MDS condition is called clonal hematopoiesis of indeterminate potential (CHIP), which increases the risk of developing MDS and, at the same time, non-malignant conditions like atherosclerosis.

In this study, I will use state-of-the-art approaches to answer the questions of why TET2-mutant stem cells exhibit clonal dominance in the bone marrow and why TET2-mutant macrophages in the peripheral blood are more inflammatory and promote atherosclerosis, and how drug treatment can reverse these phenomena: i) I will use a preclinical mouse model of CHIP and single-cell CITE-seq to determine the gene expression profiles in individual cells with and without Tet2-mutation and with and without Tyrosine kinase inhibitor (TKi) treatment. ii) Using ChIP-seq and CUT&RUN technology, I will identify the key transcriptional regulatory networks of normal and Tet2-mutant bone marrow cells and macrophages and analyze TKi treatment effects on these pathways. These studies will help to identify new therapeutic approaches that specifically eradicate the TET2-mutant cells in MDS patients and individuals with CHIP.