Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models

Abstract

Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity.

Figure 1

Weight and survival of two mouse models of leukemia in obesity. A. Weights of mice transgenic for human BCR/ABL randomized to a high-fat diet (60% of calories from fat, closed circles) or lab chow (13.5% calories from fat, open circles). B. Survival curves generated from Kaplan Meier life tables of obese (solid line) vs. control (dashed line) BCR/ABL mice. C. Weights and D. survival curves of AKR/J mice randomized to high fat (60% of calories from fat) vs. control (10% of calories from fat) diet. Weights were significantly higher in fat-fed mice in both models at all time-points after weaning (p<0.05), and survival significantly shorter (see methods, p<0.05 log rank).

Figure 2

Wet weights of thymuses (A) and spleens (B) from obese (solid) and control (open circles) AKR/J mice. C. CD4/8 expression of lymphocytes isolated from thymuses of AKR/J mice. Left bars are from obese mice, right from controls. Black – CD4+/CD8+; Hatched – CD4+/CD8−; White – CD4−/CD8+; Gray – CD4+/CD8+

Figure 3

Plasma levels of insulin, leptin, adiponectin, and IL-6 from AKR/J mice sacrificed at various ages on low (hatched bars) or high-fat diet (solid bars). *p<0.05 compared to control mice. See text for ANOVA results.