Kelly Bolton, MD, PhD

Myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are fatal diseases because they are highly resistant to therapy. Ultimately, efforts at preventing MN might be the most successful way to eradicate this disease. Clonal hematopoiesis (CH) is thought to be the origin of MN. CH is a process whereby a hematopoietic stem or progenitor cell (HSPC) acquires a mutation (alteration in the nucleic acid sequence) that leads to a growth advantage compared to normal HSPCs. CH can be detected many years prior to a person developing MN but as of yet, there are no established therapies to prevent progression of CH to MN. We hypothesize that CDK4/6 inhibition might be a potential treatment to prevent MN through halting the progression of CH. Here we seek to: 1) further characterize the potential of CDK4/6 inhibitors to prevent CH expansion through analysis of pre-existing clinical trial data; and 2) using mouse modeling evaluate the potential of CDK4/6 inhibitors to inhibit CH independent of chemotherapy. If successful, this work will justify the development of clinical trials using CDK4/6 inhibitors to prevent CH from progressing to MN in high-risk populations. In the long term, we hope to use targeted approaches to eradicate high risk CH mutations to prevent the development of MN.