Abstract 726: Effects of diet composition and timing on treatment for FLT3 positive acute myeloid leukemia
Authors: Rodriguez Megan , Figueroa Mary , Murphy Brianna , Cheng Tiewei , Fekry Baharan , Allton Kendra , Barton Michelle , Konopleva Marina , Mahan Kristin , Chandra Joya 
Published: June 2022

Acute myeloid leukemia (AML) with a mutation in the fms-like tyrosine kinase receptor 3 gene (FLT3) confers poor survival for pediatric patients, indicating a significant need to improve treatment efficacy. A significant percentage of pediatric patients consume diets high in fat and sugar content. These macronutrients modulate oxidative stress yet their impact on AML treatment is unexplored. Studies have implicated a role for BMAL1 rhythmicity, a circadian clock protein, in leukemogenesis. However, BMAL1 has not been studied in FLT3 mutant AML. Given that both nutrition and circadian rhythmicity can be modulated by behavior, we hypothesized that modulating redox and BMAL1 status through diet composition and timing would enhance treatment efficacy in an orthotopic mouse model.

In all in vivo experiments, mice were injected via tail vein with 100,000 MOLM13 luciferase labelled cells, a FLT3 AML human cell line. After engraftment was confirmed 3 days later, mice were put on diet modification regimens. In three subsequent experiments, distinct diet interventions were delivered: low fat (30%)/low sucrose (10%), low sucrose alone (10%), or an isocaloric time feeding regimen (TRF) restricted to mice’s active phase (7 PM to 7 AM). Standard chow, high sucrose diet (45%) and ad libitum feeding were controls, respectively. In each experiment, doxorubicin (2 mg/kg) or PBS was injected twice weekly via tail vein. Tumor burden was monitored via bioluminescent imaging. Reactive oxygen species (ROS) levels were assessed with flow cytometry, and changes in circadian, redox, and apoptotic protein expression were measured by western blot and mass cytometry.

On day 17, in the presence of doxorubicin, mice on a low fat/low sucrose diet showed significantly lower tumor burden compared to control. Doxorubicin induced oxidative stress was reduced in the mice fed the modified diet as demonstrated by a decrease in ROS levels in peripheral blood mononuclear cells. Even in the absence of doxorubicin treatment, the modified diet group showed significantly lower tumor burden on day 17. For mice on a low sucrose diet, changes in redox and circadian protein expression were observed on day 17. Of note, total BMAL1 protein showed a two-fold increase in spleen from the low sucrose group. In the timed feeding experiments, we observed TRF mice had significantly reduced leukemic burden on day 14. Importantly, doxorubicin efficacy was not compromised by TRF. In addition, a significant increase in total BMAL1 protein expression was observed in liver from these TRF mice on day 14.

These results point to a novel finding: diet composition and timing slows progression of FLT3 AML growth in vivo and are accompanied by BMAL1 modulation. In future studies, we aim to further define the role of circadian rhythmicity and diet composition in AML progression and identify methods to complement treatment to positively impact survival outcomes for patients diagnosed with AML.

Citation Format: Megan Rodriguez, Mary Figueroa, Brianna Murphy, Tiewei Cheng, Baharan Fekry, Kendra Allton, Michelle Barton, Marina Konopleva, Kristin Mahan, Joya Chandra. Effects of diet composition and timing on treatment for FLT3 positive acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 726.