Extinguishing the Embers: Targeting AML Metabolism

Abstract

Acute myeloid leukemia (AML) is a cancer derived from the myeloid lineage of blood cells, characterized by overproduction of leukemic blasts. Although therapeutic improvements have made a significant impact on the outcomes of patients with AML, survival rates remain low due to a high incidence of relapse. Similar to how wildfires can reignite from hidden embers not extinguished from an initial round of firefighting, leukemic stem cells (LSCs) are the embers remaining after completion of traditional chemotherapeutic treatments. LSCs exhibit a unique metabolic profile and contain metabolically distinct subpopulations. In this review, we detail the metabolic features of LSCs and how thetse characteristics promote resistance to traditional chemotherapy. We also discuss new therapeutic approaches that target metabolic vulnerabilities of LSC to selectively eradicate them.

Keywords: AML; LSC; acute myeloid leukemia; leukemic stem cells; mitochondrial metabolism; oxidative phosphorylation.

Figure 1:. Comparison of normal and leukemic myeloid hematopoietic hierarchies.

Hematopoietic stem cells (HSCs) self-renew and primarily exist in a glycolytic state during quiescence but switch to oxidative phosphorylation (OXPHOS) upon differentiation. HSCs differentiate into multipotent progenitors (MPPs), which lose the ability to self-renew but have increased frequency of cell cycle progression and differentiation activity. The MPP then differentiates to a common myeloid progenitor (CMP), which can become a megakaryocyte–erythroid progenitor (MEP), generating erythrocytes and platelets, or a granulocyte-macrophage progenitor (GMP), generating granulocytes. Both HSCs, MPPs, and CMPs can potentially become a leukemic stem cell (LSC) through the acquisition of transforming mutations. LSCs also have the capacity for self-renewal and are uniquely reliant on OXPHOS. They differentiate to produce leukemic blasts, which lose the ability to self-renew but can use both glycolysis and OXPHOS. While leukemic blasts are sensitive to traditional chemotherapy, LSCs require targeted therapies for their eradication. Created with BioRender.com.

Figure 2:. Mechanisms regulating ROS in LSCs.

Leukemic stem cells (LSCs) display several mechanisms that function to maintain low levels of reactive oxygen species (ROS). LSCs reside in the hypoxic bone marrow niche, limiting oxidative stress. Hypoxia-inducible factors (HIFs), essential to the cellular response to hypoxia, are activated even in normoxia in LSCs and niche factors such as thrombopoietin (TPO) and stem cell factor (SCF) promote HIF stabilization. FOXO transcription factors also maintain low ROS levels by regulating mitochondrial expression of superoxide dismutase (SOD2) and glutamine synthetase. Glutamine, along with cysteine, is critical to the production of glutathione, which scavenges free radicals and other ROS. FOXO TFs are also required for autophagy and mitophagy, which mitigates oxidative stress through removal of toxic proteins and damaged mitochondria. AMP kinase (AMPK), which upregulates mitochondrial fission regulator FIS1 and therefore mitophagy, is intrinsically activated in LSCs. The PML-PPARδ-FAO pathway, upregulated in LSCs, also promotes mitophagy.

Figure 3:. Metabolic features of LSCs.

A) de novo LSCs are described as metabolically inflexible as they are unable to activate glycolysis and are uniquely reliant on OXPHOS for energy production. As a result, glucose can no longer be used as a fuel source for the TCA cycle and de novo LSCs are instead reliant on amino acids as a fuel source. Amino acids enter the TCA cycle through conversion to TCA cycle intermediates such as oxaloacetate and alpha-ketoglutarate. The combination of venetoclax and azacitidine (Ven+Aza) successfully inhibits amino acid import and metabolism as well as OXPHOS, allowing de novo LSCs to be eradicated. B) Relapsed/refractory (R/R) LSCs are also unable to activate glycolysis and are also uniquely reliant on OXPHOS for energy production. While glucose is not available as a fuel source for the TCA cycle, R/R LSCs can use both amino acids and fatty acids to fuel the TCA cycle and OXPHOS. Fatty acids are converted to Acetyl-CoA through beta oxidation in the mitochondria. While Ven+Aza remains biologically active in these cells, the ability of R/R LSCs to use fatty acids as a fuel source allows for therapeutic resistance by compensating for the loss of amino acids. Created with BioRender.com.