Annie Hu
Research Mentor(s): Qing Li
Mentor Department: Medicine Division of Hematology & Oncology
Authors: Annie Hu, Timothy Liang, Ashlyn Johnson, Jolie Rosenstein, Qing Li, Morgan Jones
Session: Session 4 (1:00pm – 1:50pm)
Presentation Type: Poster 86
Abstract
Tet methylcytosine dioxygenase 2 (TET2) is a DNA demethylating enzyme and is commonly mutated across blood cancers. Prior work has demonstrated that TET2 deficiency has pleiotropic effects in the blood, impacting response to inflammatory stress, biasing hematopoietic stem cell (HSC) differentiation to the myeloid lineage, and enhancing HSC self renewal. Previous studies have shown that TET2-deficient HSCs outcompete wild type cells, indicating that TET2-deficient HSCs have enhanced fitness compared to wild type HSCs. Understanding how TET2-deficient HSCs obtain and sustain this competitive advantage promises to shape not only our understanding of HSC biology, but also offers the possibility of developing novel interventions to treat a wide spectrum of blood cancers. The frequency of blood cancers increases as a person ages, coincident with expansion of fat cells in the bone marrow. We sought to determine if this age-associated change in fat content, and therefore in potential interactions with fat, impact the TET2-deficient HSC competitive advantage. To model this in mice, we developed 4 mouse models: wild type (WT), TET2 knockout, Acetyl-CoA carboxylase 1 (ACC1) knockout, and TET2/ACC1 double knockout (DKO). ACC1 is the first and rate limiting step of de novo lipogenesis, the process through which fat is synthesized in cells. Deletion of ACC1, therefore, renders a cell completely reliant on extracellular fat. Using flow cytometry to analyze developmental hematopoiesis and bone marrow transplant to assess HSC function, we sought to determine if reliance on extracellular fatty acid uptake impacted TET2-deficient HSC self-renewal and the competitive advantage central to their leukemogenic activity.
