Obesity Accelerates T-Cell Leukemia in a Spontaneous Mouse Model.

Obesity is associated with an increased risk of developing several types of cancer, including leukemia. As obesity is associated with alterations in a large number of physiological, physical, and lifestyle parameters, investigating this association is difficult in human studies. However, AKR/J mice are susceptible to diet-induced obesity and develop spontaneous T-cell leukemia starting at 5–6 months of age due to recombinant retroviruses that target thymocytes. Therefore, the present studies utilized this mouse model to test the following two hypotheses: 1. Diet induced obesity causes an accelerated presentation of T-cell leukemia in AKR/J mice, and 2. Obesity causes detectible alterations in T-cell maturation in AKR/J mice prior to the onset of leukemia. In Experiment 1, we determined the effect of obesity on the onset of T-cell leukemia by randomizing 24 male AKR/J mice to either a high fat (60% of calories from fat) or control diet (10% of calories from fat) at 4 weeks of age. Mice were classified as leukemic when they showed signs of clinical illness (labored breathing, dramatic weight loss, or lethargy) and they were sacrificed shortly thereafter. In Experiment 2, we characterized T-cell maturation in 24 additional male AKR/J mice randomized to either diet and sacrificed in groups of 3 at various time points prior to leukemia development. At sacrifice, thymuses were weighed and thymocytes analyzed by FACS for markers of T-cell differentiation, including CD4/ CD8 and T-cell receptor (TCR) αβ/γδ expression. By 6 weeks on the high-fat diet, mice in both experiments weighed significantly more than their littermates on the control diet (27.7±1.8 vs. 24.5±1.8g; p<0.001). This weight difference persisted throughout the study (53.8±2.8 vs. 45.5±3.9g at 6 months of age, p<0.001). In Experiment 1, obese AKR/ Js developed spontaneous thymoma and were sacrificed significantly earlier than their non-obese counterparts (Figure: median survival 237 vs. 310 days, p<0.05, log rank). In Experiment 2, we found no significant differences in thymus weights between diet groups (p=n.s. for all timepoints). Flow cytometry analyses of thymuses from the pre-leukemic mice, as characterized by CD4/CD8 and TCR αβ/γδ expression, demonstrated a characteristic pattern of maturing T-cell subgroups. This pattern was not different between the experimental groups. Thymuses from leukemic mice showed alterations in this pattern, characterized by expansion of specific populations (e.g. CD4/CD8 −/−), which differed from mouse to mouse. Again, diet group did not appear to affect which population predominated in the leukemic mice. These findings demonstrate that obesity accelerates spontaneous T-cell leukemia in the AKR/J mouse. However, diet-induced obesity does not appear to affect T-cell maturation prior to the onset of leukemia, at least not as defined by expression patterns CD4, CD8, and TCR αβ/γδ. Neither does obesity appear to promote the outgrowth of a specific leukemia population. Thus, the mechanism whereby obesity accelerates T-cell leukemia remains unclear. It is possible that obesity affects some other stage of leukemogenesis, such as affecting retroviral recombination or accelerating the proliferation of leukemia cells after they are transformed, but further work is needed to address this. Figure Figure