# Defining and leveraging nutritional and circadian dependencies to augment acute leukemia therapy

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $253,875

## Abstract

PROJECT SUMMARY
 Nearly 11,000 adults and children are projected to die in the United States in 2019 due to acute myeloid
leukemia (AML), a genetically heterogeneous blood cancer. Mutations in the FMS-like tyrosine kinase 3 (FLT3)
gene, such as an internal tandem duplication (FLT3-ITD) occur in roughly 25% of patients, and constitute the
most commonly seen genetic alteration in this disease. Patients who are FLT3-ITD positive face poor
prognosis relative to other AML patients despite the development and clinical use of targeted therapies such as
kinase inhibitors. Weight status (overweight and obesity) and poor nutritional status have also been correlated
with inferior patient outcome, increased treatment-related toxicities, and an increase in abandonment of
therapy3,4,7. Diet quality has not been well studied as a determinant of these poor outcomes in AML. Using
orthotopic xenograft mouse models for FLT3-ITD AML, we find that leukemia burden is reduced when
a n t h r a c y c l i n e t h e r a p y is combined with a low fat/low sugar diet. An understudied aspect of diet is its
timing 11-13 and its impact on the internal circadian clock, disruption of which has been linked to cancer14-18.
Recent data has implicated proteins that control circadian clock in survival of acute myelogenous leukemia
cells, as being essential for leukemia stem cell survival. In particular, the BMAL1 protein is required for AML
cell growth, but its modulation has not been studied in the context of chemotherapies routinely used for
leukemia treatment. We hypothesize that focused and specifically timed dietary interventions can
improve chemotherapy efficacy. This represents a relatively inexpensive intervention that can be
implemented globally provided the interventions are defined, implementation is feasible and there are
biomarkers to follow to assess whether the interventions are having an impact.
 Using mouse models for leukemia to deliver t h e s e specific interventions in the setting of AML
treatment, and assessing molecular changes will provide the needed preclinical data to justify inclusion of
energy balance interventions into the treatment plan and inform the design of effective interventions in
patients. Low fat or low sugar diets have been shown to have anti-inflammatory effects, which may be linked
to reduced oxidative stress through gene expression and epigenetic mechanisms. Indeed, we find that redox
modulation and macrophage/dendritic cell ratio are altered by dietary sucrose. We will further define these
changes in the context of augmentation of AML therapy and as biomarkers for alterations in energy balance
through the treatment continuum. In addition, we will implement restricted feeding paradigms, which are shown
to alter circadian clock activity, to determine whether the quality and timing of nutritional impact influences the
effects of treatment on AML. We will:
Aim 1: Identify diet regimens that enhance therapy efficacy in AML FLT3-ITD bearing mouse ...

## Key facts

- **NIH application ID:** 10071353
- **Project number:** 1R21NR019532-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Joya Chandra
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $253,875
- **Award type:** 1
- **Project period:** 2020-08-07 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071353

## Citation

> US National Institutes of Health, RePORTER application 10071353, Defining and leveraging nutritional and circadian dependencies to augment acute leukemia therapy (1R21NR019532-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071353. Licensed CC0.

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