# Therapeutic Targeting of Human AML Stem Cells

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2022 · $912,708

## Abstract

Summary
This proposal is focused on the development of improved therapies for acute myeloid leukemia (AML).
The central premise of our all our work is that AML is driven by a biologically distinct leukemia stem cell
(LSC) population. While the conceptual importance of targeting leukemic disease at its root is clear,
studies in recent years have demonstrated that the inherent intra-patient heterogeneity of LSC
populations makes complete eradication a very challenging objective for most patients. Our studies
have therefore attempted to identify common foundational properties of primary human LSCs that can
employed in the development of therapeutic strategies in the hope that intrinsic heterogeneity can be
overcome. Of particular interest, we have described distinct metabolic properties in LSCs, that provide
new opportunities for intervention. Specifically, inhibition of BCL2 acts to inhibit oxidative
phosphorylation in LSCs, resulting in selective eradication of the LSC population. Recent translation
of this observation to clinical studies has demonstrated strong efficacy for newly diagnosed AML
patients, and appears to be on the verge of altering the current standard of care. Despite these exciting
advances though, relapse remains common and further elucidation of LSC properties is essential. To
this end, we have recently begun to describe the mechanisms that drive relapse of AML patients
following treatment with a BCL2 inhibitor. These studies have identified entirely unexpected and new
aspects of LSC biology that have important ramifications for our basic understanding of AML, as well
as the design of improved therapeutic regimens. Specifically, we have demonstrated that at least two
distinct LSC populations can co-exist in the same patient. The genetic, epigenetic, and metabolic
properties of co-resident LSC subpopulations can vary, giving rise to differing levels of drug
responsiveness. The focus of our studies going forward will be to understand and exploit these findings
towards the goal of improved outcomes for AML patients.

## Key facts

- **NIH application ID:** 10478294
- **Project number:** 5R35CA242376-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Craig T. Jordan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $912,708
- **Award type:** 5
- **Project period:** 2020-09-08 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478294

## Citation

> US National Institutes of Health, RePORTER application 10478294, Therapeutic Targeting of Human AML Stem Cells (5R35CA242376-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10478294. Licensed CC0.

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