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. Cancer Prev Res; 3(10); 1259-64. ©2010 AACR.

Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment

“…43 It has been demonstrated that growth factors, including leptin, insulin, and interleukin-6, are highly expressed in the serum of obese compared with lean mice. 41 In another report, leptin was shown to revert the proapoptotic and antiproliferative effects of a-linoleic acids in breakpoint cluster region-abelson-positive leukemic cells, suggesting a role for the phosphatidylinositide 3-kinase pathway in this process. 44 In this report, we demonstrated leptin overexpression in AML and ALL BM.…”

“…In another report, diet-induced obesity accelerated ALL progression in 2 murine models. 41 Obesity is known to associate with increased risk for numerous types of cancers in adults. 42 Moreover, obese cancer patients have poorer outcomes than their leaner counterparts.…”

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

“…Patients with obesity and ALL have worse outcomes 46,48 than patients with ALL but without obesity, and patients with ALL have a high risk of obesity after treatment 42,49 . In addition, diet-induced obesity can accelerate the development of ALL in mouse models 50 . Obesity is characterized by leptin resistance that is usually marked by elevated leptin levels but attenuated LEPR signaling 51 .…”

Animal Models of Lymphoproliferative Disorders Focusing on Waldenström's Macroglobulinemia

“…For example, Yun et al (2010) 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.…”