Abstract
Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, AML cells gain metabolic plasticity and rapidly outcompete normal hematopoietic cells. This review aims to decipher the diverse metabolic strategies and the underlying oncogenic and environmental changes that sustain continuous growth, mediate redox homeostasis and induce drug resistance in AML. We revisit Warburg’s hypothesis and illustrate the role of glucose as a provider of cellular building blocks rather than as a supplier of the tricarboxylic acid (TCA) cycle for energy production. We discuss how the diversity of fuels for the TCA cycle, including glutamine and fatty acids, contributes to the metabolic plasticity of the disease and highlight the roles of amino acids and lipids in AML metabolism. Furthermore, we point out the potential of the different metabolic effectors to be used as novel therapeutic targets.
Highlights
Acute myeloid leukemia (AML) is characterized by abnormal proliferation of undifferentiated and non-functional hematopoietic cells in the bone marrow [1]
The authors of this study demonstrated that urothelial carcinoma-associated 1 (UCA1) functioned as a competing endogenous RNA of miR-125a, which in turn positively regulates the expression of the miR-125a-target hexokinase 2 (HK-2) [39]
Mitochondria are the central site in the cell, where metabolic pathways that feed from carbohydrates, amino acids and fatty acids (FAs) converge into the tricarboxylic acid (TCA) cycle and further into an electron transport chain (ETC) that provides energy through oxidative phosphorylation (OXPHOS) (Figure 3)
Summary
Acute myeloid leukemia (AML) is characterized by abnormal proliferation of undifferentiated and non-functional hematopoietic cells (the leukemic blasts) in the bone marrow [1]. Deciphering the molecular landscape of AML has helped to elucidate the cellular pathogenesis of the disease and to guide treatment decisions according to individual prognosis prediction (reviewed in [12,13]) Despite these advances, the knowledge of AML driver mutations only rarely led to the discovery of novel drugs, at least until recently. Allogeneic hematopoietic stem cell (HSC) transplantation is the most important therapy to prevent relapse after initial successful treatment (reviewed in [12,13]) These therapeutic strategies are, utterly unsatisfactory: despite significant progress, mainly due to the increased ability to successfully treat opportunistic infectious diseases, to provide supportive care, and to master the complications of allogeneic bone marrow transplantation, the majority of AML patients still die from this disease [1]. There is no doubt that in the course of clonal evolution, AML clones in the bone marrow are being trained by their microenvironment to optimally adapt to regulatory circuits of cell signaling and gene regulation, and to optimally adapt to metabolic conditions—displaying a high metabolic plasticity that we only begin to understand
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