(P26-064-25) Dietary Avocatin B Modulates Fatty Acid Oxidation to Impart Stem Cell Protection in Bone Marrow

Objectives: Hematopoietic stem cells (HSCs) maintain production of all functional blood cells and are located within the bone marrow. In pathological conditions, such as obesity or leukemia, changes in these and progenitor cells contribute to disease pathophysiology. In this study, we examined the impact of metabolic modulation of stem cells within the bone marrow during diet-induced obesity (DIO) and leukemia relapse. Avocatin B (AvoB), an inhibitor of fatty acid oxidation (FAO), was provided in the diet and its impact on stem cells using two disease models was tested.

Methods: In DIO studies, C57BL/6J mice were placed on a high fat-diet (HFD) (60% kcal from lard; Research Diet D12492; Research Diets, USA) or a standard diet (10-13% kcal from fat; Teklad 2014; Envigo, USA) for eight weeks. At week eight, mice continued their respective diets but were administered AvoB (100mg/kg body weight -b.w.) or vehicle by gavage twice weekly for 5 weeks.

In leukemia relapse models, human-derived leukemia cells were injected into NSG mice. After engraftment was established (i.e., human cells in mouse bone marrow), mice were treated with standard chemotherapy (i.e., AraC; 50mg/kg for 5 days) and then placed on AvoB-enriched or control diets.

Results: Compared to control-fed, HFD diets significantly reduced the number of normal bone marrow stem cells (i.e., Lin^-Sca-1⁺c-Kit⁺ (LSK) cells, t₁₀=4.9; p< 0.001, and short term (ST)-HSCs: t₁₀=2.8; p< 0.01) that coincided with an increase in myeloid progenitors (t₃=3.724; p< 0.05). Mice fed AvoB enriched diets had a significant attenuation of DIO-induced losses in ST-HSC and LSK cells (t₇ = 1.9; p< 0.05) as well as a recovery back to normal for myeloid progenitors (t₄; 4.3; p< 0.01).

Tumor burden in the bone marrow was tracked over time by aspirates and flow cytometry. Compared to control-fed, mice on AvoB-enriched diets had significantly less leukemia burden at endpoint (t₁₆=2.2, p< 0.05) and a significant reduction in the leukemia cell growth rate (t₁₈=2.6; p< 0.01).

Conclusions: Taken together, dietary AvoB imparts protection in the bone marrow against DIO and leukemia relapse.

Funding Sources: Research was supported by grants to P.A.S. by the American Institute for Cancer Research and the University of Guelph and to N.A. by Mitacs Canada.