# Therapeutic Targeting of MDS Stem Cells

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2021 · —

## Abstract

The goal of this application is to elucidate properties of myelodysplastic syndrome (MDS) stem
cells that will lead to improved strategies for therapeutic targeting. In the context of MDS,
malignant stem cells are thought to reside at the heart of disease, driving progression and
ultimately transformation to acute myeloid leukemia (AML). While some drugs have activity in
MDS, few if any clinically approved agents are known to efficiency eradicate MDS stem cells.
Thus, our studies have focused on fundamental aspects of cellular 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 MDS stem cells are similarly unique
and employ metabolic mechanisms that are distinct from bulk MDS cells as well as normal
stem/progenitor cells. Indeed, our preliminary data show that like normal HSCs, most MDS
stem cells are quiescent and reside in a state of relatively low reactive oxygen species (termed
“ROS-low”). Intriguingly though, during pathogenesis MDS stem cells shift to an energy
metabolism phenotype characterized by preferential reliance on oxidative phosphorylation.
During the same transitional phase, MDS stem cells also strongly up-regulated protein synthesis
pathways. These distinct biological properties render MDS stem cells susceptible to therapeutic
agents such as venetoclax and omacetaxine. Indeed, our preclinical modeling studies have
been so successful with these agents that two new clinical trials have been developed to test
their use for high-risk MDS. Both trials recently opened and are now accruing. For the current
proposal we intend to perform a detailed analysis of MDS stem cells in the patients treated from
these trials. We will also conduct further preclinical modeling to better characterize the
mechanism by which MDS stem cells can be selectively eradicated. In addition to high-risk
stages of disease, our studies will be extended to include patients with low and intermediate risk
MDS. Taken together, the proposed research will elucidate the key metabolic pathways that
mediate survival of MDS stem cells and identify novel strategies for treatment of MDS patients.

## Key facts

- **NIH application ID:** 10045509
- **Project number:** 5I01BX004768-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Craig T. Jordan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045509

## Citation

> US National Institutes of Health, RePORTER application 10045509, Therapeutic Targeting of MDS Stem Cells (5I01BX004768-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10045509. Licensed CC0.

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