Abstract
Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. Adipocytes are prevalent in the BM stroma and increase in number with age. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). FAO reactions generate acetyl-CoA from fatty acids under aerobic conditions and, under certain conditions, it can cause uncoupling of mitochondrial oxidative phosphorylation. Recent experimental evidence indicates that FAO is associated with quiescence and drug-resistance in leukemia stem cells. In this review, we highlight recent progress in our understanding of fatty acid metabolism in AML cells in the adipocyte-rich BM microenvironment, and discuss the therapeutic potential of combinatorial regimens with various FAO inhibitors, which target metabolic vulnerabilities of BM-resident, chemoresistant leukemia cells.
Highlights
Reviewed by: Kristian Bowles, University of East Anglia, United Kingdom Stuart Rushworth, University of East Anglia, United Kingdom
This review summarizes the current understanding of the role of fatty acid metabolism in Acute myeloid leukemia (AML) cells in the adipocyte-rich bone marrow (BM) microenvironment they occupy, and relationships between fatty acid metabolism and leukemic stem cells (LSCs) focusing on the potential molecular mechanisms through which AML
LSCs are a subpopulation of AML cells in the BM microenvironment that become resistant to drugs by entering a quiescent state, which is induced by growth factor signaling, epigenetic regulation, and altered metabolism [11, 39]
Summary
Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). Glucose is metabolized to pyruvate through glycolysis during normal and pathological conditions, and, in the presence of oxygen, pyruvate can be further metabolized to acetyl-CoA that is oxidized in the Krebs cycle to drive oxidative phosphorylation (OXPHOS) and ATP generation. This process can generate 36 moles of ATP per mole of glucose that is 18 times more than that generated by glycolysis alone.
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