Kathryn Dupras
Research Mentor: Qing Li
Mentor Department: Medicine Division of Hematology & Oncology, Medicine
Author(s): Kathryn Dupras, Koral Campbell
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 47
Abstract
Aged hematopoietic stem cells (HSCs) are associated with an increase in proliferation and self-renewal capacity. Aged HSCs often accumulate somatic mutations associated with an increased risk of hematologic malignancies such as acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Despite recent developments in novel targeted therapies, very few patients are cured. HSCs that carry these mutations often show improved proliferation and self-renewal capacity, a condition called clonal hematopoiesis (CH). CH can occur without producing overt signs of disease. Mutations in TET2 are among the most common CH-associated mutations and are frequently observed in hematologic malignancies, often leading to increased inflammation and promoting clonal expansion. Understanding how hematologic malignancies develop can help target an early stage of disease and ultimately slow progression. Obesity has been linked to an increased risk of leukemogenesis. Given the rate of obesity in elderly individuals, it is important to understand its contribution to CH progression. To investigate the impact of metabolic stress on CH, we exposed blood-specific Mx1-Cre Tet2 knockout (KO) mice to high-fat diet (HFD) for 20 weeks. This model has shown a trend towards increased splenic size, reduced bone marrow (BM) HSCs, and myeloid skewing. Because the Mx1-Cre model requires inflammatory stimulation to induce the mutation, and CH is an inflammatory condition, we also utilized an embryonic Vav1-Cre Tet2 KO model. Interestingly, in the Vav1-Cre model, there were no early signs of disease. Competitive transplants showed that HSCs from Tet2 KO mice on HFD had a competitive advantage and myeloid bias compared to the wild-type cells. Secondary transplant revealed that the Tet2 KO HSCs exposed to HFD were non-functional and unable to repopulate the BM a second time. This suggests that HFD promotes an early-aging phenotype where HSCs have altered differentiation capacity, but reduced functionality.
