A Leukemic Target with a Thousand Faces: The Mitochondria

Abstract

In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years remains unfortunately low. Indeed, the high heterogeneity of AML clones with distinct metabolic and molecular profiles allows them to survive the chemotherapy-induced changes, thus leading to resistance, clonal evolution, and relapse. Moreover, leukemic stem cells (LSCs), the quiescent reservoir of residual disease, can persist for a long time and activate the recurrence of disease, supported by significant metabolic differences compared to AML blasts. All these points highlight the relevance to develop combination therapies, including metabolism inhibitors to improve treatment efficacy. In this review, we summarized the metabolic differences in AML blasts and LSCs, the molecular pathways related to mitochondria and metabolism are druggable and targeted in leukemia therapies, with a distinct interest for Venetoclax, which has revolutionized the therapeutic paradigms of several leukemia subtype, unfit for intensive treatment regimens.

Keywords: AML; AML blasts; AML–LSC; Venetoclax; metabolism; mitochondria; personalized therapies.

Figure 1

Metabolic differences between LSCs and blasts in AML. Graphic representation of metabolic differences between AML–LSCs cells and AML blasts. (A) AML–LSCs are dependent on OXPHOS, crucial for high ATP production, exhibit low ROS level and use amino acid and fatty acid metabolism to sustain the citric acid cycle. (B) On the contrary, AML blasts are more reliant on glycolysis for ATP production and have a higher metabolic activity. In addition, blasts have a higher number of mitochondria and a higher ROS level. Abbreviation: LSCs: leukemic stem cells, TCA: tricarboxylic acid; FAO: fatty acid oxidation; OXPHOS: oxidative phosphorylation; ATP: adenosine triphosphate; FIS1: mitochondrial fission 1 protein; GPx-3: Glutathione peroxidase 3; ROS: reactive oxygen species; AA: amino acids; PPP: pentose phosphate pathway; I–V: complexes of electron transport chain. Red and blue arrows in the boxes correspond to increase and decrease respectively. The figure is created with “https://biorender.com/ (accessed on 20 July 2023)”.

Figure 2

Mechanism of action of Venetoclax. The BH3-mimetic Venetoclax interacts selectively with BCL2 in the BH3-binding grooved pocket, preventing its interaction with the pro-apoptotic proteins Bad and Bax. The main consequence is the release of cytochrome c from the mitochondria, and the formation of pores in the mitochondrial membrane, triggering a cascade of events that ultimately leads to apoptosis. To avoid Venetoclax effects, different forms of resistance may be activated by leukemic cells, including Bcl-2 overexpression, Bcl-2 mutations, or deregulation of other anti-apoptotic proteins. Abbreviations: Cyto C: cytochrome c.