Abstract 2817: Enriched environment inhibits progression of acute myeloid leukemia
Authors: Xiao Run , Bergin Stephen M. , Caligiuri Michael A. , Cao Lei 
Published: July 2017

Abstract
Background: Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our recent work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity (DIO), enhanced insulin sensitivity, lower serum IGF-1 and leptin levels, higher serum adiponectin level, enhanced immune functions, and inhibition in melanoma and colon cancer growth. We have teased out one key mechanism underlying the anticancer effect of EE: the stimulation of brain-derived neurotrophic factor (BDNF) expression in the hypothalamus and the subsequent activation of a specific neuroendocrine axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis. However, the EE’s effects on hematologic malignancy are largely unknown. Here we generalized this intervention to acute myeloid leukemia (AML) using the MLL-partial tandem duplication (PTD) and Flt3-internal tandem duplication (ITD) double knock-in mouse (MllPTD/WT:Flt3ITD/WT) that recapitulates features of counterpart human AML.
Methods: For transplantation of AML cells, Ly5.2 spleen cells isolated from leukemic MllPTD/WT: Flt3ITD/WT mice were resuspended in PBS. Syngenic Ly5.1 recipient C57Bl/6 male mice (CD45.1+) were sublethally irradiated (400 cGy). Five to six hours later, leukemic cells (4×106 per mouse) were injected through the lateral tail vein. Those mice were randomly assigned to either standard laboratory cage (SE) or EE housing. To monitor AML progression, white blood cell (WBC) counts were measured from peripheral blood. Survival experiments were performed.
Results: EE mice had a median survival 14% longer than SE mice (SE = 36 ± 1.1 days, EE = 41 ± 1.2 days, p = 0.038) and improved hazard rate (log-rank test z = 1.99, p = 0.047). Based on WBC counts (&gt;10.9 k/µL), 100% of SE mice and 80% of EE mice had apparent AML at three weeks post injection. At this time point, EE had a substantially lower WBC counts (SE = 76.9 k/µL, EE = 26.4 k/µL, p = 0.0006). WBCs from EE mice had lower neutrophil, monocytes, eosinophils and basophils counts, but had similar lymphocytes, resulting in a reduced neutrophil to lymphocyte ratio. Red blood cell (RBC) and platelet data were the same except for a slightly reduced mean corpuscular hemoglobin concentration (MCHC) in EE mice. At four weeks, EE mice were substantially more active and mobile than SE mice. At five weeks, at which point 3 SE and 5 EE mice remained alive, WBC counts remained lower in EE mice.
Conclusions: This preliminary work demonstrated EE substantially improved progression-free survival and conferred a significant survival benefit. We will elucidate the underlying mechanisms of EE’s anti-AML effect by assessing metabolic modulation and immune regulation.
Citation Format: Run Xiao, Stephen M. Bergin, Michael A. Caligiuri, Lei Cao. Enriched environment inhibits progression of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2817. doi:10.1158/1538-7445.AM2017-2817