Effects Of Obesity And Exercise On Bone Marrow And Leukemia Cells Following Radiation

Abstract

Radiation-induced leukemia is a serious late effect of radiation therapy partially due to long-term alterations in the bone marrow (BM) environment. Obesity and sedentary lifestyles, two host factors that remodel the bone marrow, are common amongst cancer survivors and linked to increase leukemia risk. Whether alterations to the bone marrow environment induced by obesity and physical activity alter leukemia risk following ionizing radiation (IR) exposure remains unknown. PURPOSE: Determine how exercise training and obesity modulate the BM environment and leukemia blast viability following sub-lethal IR exposure. METHODS: 4 week old CBA mice were fed a control (CON; n=20) or 45% high fat diet (HF; n=20). At 9 weeks old, CON and HF mice were divided into sedentary (SED, n=10) or exercise groups (EX, n=10). At 13 weeks, mice were administered a uniform radiation dose of 3 Gy and continued their specific diet and exercise regimen for 4 weeks. BM stromal cells were quantified by flow cytometry and marrow adipose tissue (MAT) was determined by μCT. Conditioned media (CM) from isolated BM stromal cells was analyzed by cytokine array and applied to the KG-1 leukemia cell line to assess cell viability by MTT assay. RESULTS: The number of mesenchymal stromal cells in CON+EX increased compared to CON+SED (p<0.05). EX increased the quantity of osteoblasts and endothelial progenitor cells compared to SED mice (both p<0.05). EX reduced MAT compared to SED, even in the presence of HF diet following sub-lethal IR (p<0.05). Inflammatory cytokines were also increased in the CM of HF-SED compared to CON-SED, and this effect was reduced with EX. CM from HF mice increased KG-1 viability, but not CM from EX (p<0.05). CONCLUSION: Overall, exercise increased BM stromal cell content and reduced BM inflammation while obesity increased BM adiposity and leukemia cell viability. These data suggest that exercise may be a therapeutic intervention to reduce secondary leukemias following radiation therapy, particularly in obese cancer survivors.