Morgan Jones, M.D., Ph.D.
2021 Funding recipient
Exploring the impact of dietary stress on the progression of clonal hematopoiesis
EvansMDS Young Investigator Award
Myelodysplastic syndrome (MDS) is a cancer of the bone marrow typically affecting individuals over the age of
60. Increasing evidence from the past decade has shown that, in at least a subset of individuals, MDS can arise from a premalignant state termed clonal hematopoiesis of indeterminate potential (CHIP). In CHIP, mutations that we often see in MDS and leukemia are detected in the blood of some elderly people, but these individuals do not have a malignancy. Since not every person with CHIP develops MDS or other bone marrow cancers, understanding mechanisms that contribute to the progression of CHIP to cancer may result in the development of new treatment strategies relevant to both treating MDS itself and perhaps in preventing the progression from CHIP to cancer. We have found that loss of Tet2, the second most common gene mutated in CHIP, results in a unique sensitivity to high fat diet feeding. In mice deficient in Tet2, high fat diet feeding results in the rapid development of bone marrow abnormalities suggestive of progressive disease. We find that this progression coincides with increased expression of the protein CD36. CD36 is a unique protein that is involved in both cellular fat uptake and inflammatory signaling. In this proposal we will seek to address if CD36 is required for progressive disease in our CHIP model and characterize inflammatory abnormalities in this system that likely contribute to disease progression. This work promises to not only offer insight into mechanisms through which premalignant CHIP progresses to overt malignancy, but also to identify potential pathways that may be targeted to prevent this progression and/or treat existing disease.