# Characterization and targeting of leukemia stem cell metabolism

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $491,936

## Abstract

Project Summary
The goal of this application is to elucidate properties of human leukemia stem cells (LSCs) that
will lead to improved strategies for therapeutic targeting. Specifically, in the context of acute
myelogenous leukemia (AML), LSCs are thought to reside at the heart of disease, driving
progression and relapse. While many drugs have activity in AML, few if any clinically approved
agents are known to efficiency eradicate LSCs. Thus, our studies have focused on the
fundamental property of energy metabolism as a potential entry point for developing novel
therapies. It has become increasingly clear that normal hematopoietic stem cells (HSCs)
display unique metabolic properties that distinguish them from other cells in the hematopoietic
system. We propose that AML stem cells will be similarly unique and employ metabolic
mechanisms that are distinct from bulk AML cells as well as normal stem/progenitor cells.
Indeed, our preliminary data show that like normal HSCs, most LSCs reside in a state of
relatively low reactive oxygen species (termed “ROS-low”). Further, we show that the metabolic
sensor AMPK is preferentially activated in the ROS-low LSC population, and is responsible for
modulating energy metabolism as reflected in the use of fatty acid oxidation as well as steady-
state levels of NADPH. Importantly, genetic inhibition of AMPK is sufficient to dramatically
reduce the functional ability of LSCs. These data lead us to hypothesize that LSCs
preferentially reside in a distinct metabolic condition characterized by a ROS-low status and
activation of AMPK. Further, we propose that modulation of AMPK (and related pathways) can
be employed to “push” LSCs out of the ROS-low state, thereby reducing their fitness and/or
rendering them more susceptible to targeting by available therapeutic agents. To test these
theories, we will perform a detailed metabolomic analysis of primary human AML specimens in
order to examine relative utilization of energy pathways in primitive cell types. These studies
will focus in particular on the role of AMPK. We will also perform drug discovery/development
studies to create improved small molecule inhibitors of AMPK. Taken together, the proposed
studies will elucidate the key metabolic pathways that control energy metabolism in LSCs and
identify novel strategies for therapeutic targeting of the LSC population.

## Key facts

- **NIH application ID:** 9966891
- **Project number:** 5R01CA200707-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Craig T. Jordan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,936
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966891

## Citation

> US National Institutes of Health, RePORTER application 9966891, Characterization and targeting of leukemia stem cell metabolism (5R01CA200707-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9966891. Licensed CC0.

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