Abstract 2584: Leukemia latency in the mCG-PML-RARα mouse model is impacted by sex and obesity

Abstract

Abstract Human leukemias have been reported to show sexual dimorphism in both incidence and behavior. However, few studies of this observation have been conducted in animal models. We used the C57BL/6J mouse, genetically engineered to contain the PML-RARA fusion gene at the mouse cathepsin G (mCG) locus, as a model (B6.mCG-PML-RARα) of acute promyelocytic leukemia (APL) to interrogate the impact of sex and diet variation on disease latency as measured by leukemia-free survival. At 30 days of age, control (WT) and mutant (mCG+/PR) mice were separated by sex and provided with high fat (HF) [57% coconut oil fat] or low fat (LF) [10% coconut oil fat] diets. Mice were followed with serial blood collections and sacrificed when peripheral blood revealed signs of leukemia development including elevated granulocytes (WBC >20 K/μL), anemia (Hb <11 g/dL), and thrombocytopenia (PLT <600 K/μL). At necropsy, leukemic mice were noted to have marked splenomegaly (0.73±0.40 g) compared to controls (0.30±0.19 g). However, splenomegaly was not affected by diet in WT mice, as spleen size was consistent in both HF and LF diet-fed animals. mCG+/PR male mice fed HF diets showed greater weight gain and were significantly (P<0.001) heavier than mCG+/PR male mice fed LF diets (45.1±6.6 g versus 31.3±2.9 g at 150 days on diet). Female mCG+/PR mice fed HF diets showed greater weight gain than female mCG+/PR mice fed LF diets (31.8±5.5 g versus 23.2±1.9 g at 150 days on diet). In addition, mCG+/PR male mice fed HF diets were significantly heavier than female mCG+/PR mice fed HF diets (45.1±6.6 g versus 31.8±5.5 g at 150 days on diet). This sexual dimorphism in weight accumulation has been previously noted and attributed in part to ovarian function. The longest latency for the appearance of APL was shown in female mCG+/PR mice fed LF diets, where a median leukemia-free survival (MLFS) of >425 days was observed. In contrast, male mCG+/PR mice fed LF diets showed a reduced MLFS of 360 days of age, indicating a difference in latency of 65 days, thereby demonstrating sexual dimorphism in the appearance of APL. HF diet accelerated the appearance of APL in both female (MLFS = 277 days of age) and male mCG+/PR mice (MLFS = 277 days of age), which also displayed a difference in latency of 65 days. Thus, HF diet accelerated appearance of APL by 148 days in male and 148 days in female mCG+/PR mice. There were no signs of leukemia development in WT mice on either HF or LF diets. There was no splenomegaly observed in WT mice on either HF or LF diets. Thus, although HF diet and obesity accelerate the onset of APL in B6.mCG-PML-RARα mice, sexual dimorphism remains, with females showing extended latency compared to males under conditions of both HF and LF diets. Overall, our studies provide a robust mouse model to study the mechanisms by which sex impacts leukemia latency, as well as demonstrate that obesity accelerates leukemia development without affecting sexual dimorphism. Citation Format: John W. Kincaid, Annie E. Hill-Baskin, Nathan A. Berger. Leukemia latency in the mCG-PML-RARα mouse model is impacted by sex and obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2584.