As people age, their risk of developing blood cancers rises dramatically, yet the biological reasons for this vulnerability remain poorly understood. Aging is accompanied by chronic, low-grade inflammation, which is often called “inflamm-aging”, that alters the bone marrow environment where blood-forming stem cells reside. These stem cells are not all the same: with age, they diversify into subpopulations that respond very differently to inflammatory signals. At the same time, many older individuals acquire leukemia-associated mutations in their blood stem cells, a condition known as clonal hematopoiesis, which increases cancer risk but does not always lead to disease. What determines whether these mutated cells remain harmless or progress toward cancer is unknown. Identifying which aging stem cell populations are most susceptible to malignant transformation is a critical unmet challenge, and solving it could open the door to preventing blood cancers before they take hold.
This project will dissect how inflammatory signaling reshapes the aging hematopoietic stem cell (HSC) landscape and creates cellular niches that favor cancer-associated mutations. Focusing on TNFα–NFκB signaling and DNMT3A mutations, the most common genetic alteration in clonal hematopoiesis, the team will integrate single-cell transcriptomic analyses of aged human bone marrow with mechanistic studies in genetically engineered mouse models. By identifying an inflammatory yet dormant HSC subset that gains a competitive advantage when DNMT3A is disrupted, the research aims to define a previously unrecognized reservoir for blood cancer initiation. Functional transplantation assays will directly test the transformation potential of these cells. The resulting molecular profiles will enable the development of blood-based markers to identify high-risk individuals and inform targeted anti-inflammatory interventions, laying the groundwork for the first preventive strategies against age-related blood cancers.