# Metabolic mechanisms of venetoclax resistance in acute myeloid leukemia stem cells

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $368,502

## Abstract

Acute myeloid leukemia (AML) is thought to arise when early hematopoietic stem or progenitor
cells acquire mutations leading to the development of leukemia stem cells (LSCs). Failure to fully
eradicate LSCs using conventional chemotherapy is responsible for disease progression and
relapse, which is the main cause of death in AML. Therefore, strategies that more effectively
eradicate LSCs have the potential to be highly significant and to address an urgent unmet clinical
need.
Recent clinical studies using a combination of the BCL-2 inhibitor venetoclax with azacitidine
(ven/aza) have demonstrated remarkable results for elderly AML patients, with a high frequency
of deep and durable complete remissions. These outcomes suggest that the regimen is targeting
the LSC population in vivo. Our laboratory studies have shown that the central molecular
mechanism driving eradication of LSCs relies upon inhibition of oxidative phosphorylation
(OXPHOS). Specifically, LSCs in newly diagnosed patients utilize catabolism of amino acids as
the primary fuel to drive OXPHOS. The ven/aza regimen reduces amino acid metabolism, thereby
inhibiting OXPHOS and leading to LSC death. However, some AML patients are refractory or
acquire resistance to the ven/aza regimen. Thus, the goal of this proposal is to elucidate the
mechanisms by which LSCs become resistant to ven/aza therapy. We propose that there are at
least 3 mechanisms leading to drug resistance, each involving metabolic compensation that
circumvents the use of amino acid metabolism as a means to fuel OXPHOS. Our studies will
involve detailed analysis of each mechanism, with the objective of defining clinical therapies
designed to restore sensitivity to ven/aza and/or to target metabolic mechanisms required for LSC
survival.

## Key facts

- **NIH application ID:** 9913861
- **Project number:** 1R01CA243452-01A1
- **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:** $368,502
- **Award type:** 1
- **Project period:** 2019-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913861

## Citation

> US National Institutes of Health, RePORTER application 9913861, Metabolic mechanisms of venetoclax resistance in acute myeloid leukemia stem cells (1R01CA243452-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9913861. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*