Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML

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.

Keywords: adipocyte; bone marrow microenvironment; fatty acid metabolism; fatty acid oxidation; therapy resistance.

Figure 1

The bone marrow microenvironment reprograms energy metabolism in AML. AML cells utilize multiple metabolic pathways for energy production, glycolysis, oxidative phosphorylation (OXPHOS), and if fatty acid is available, also undergo fatty acid oxidation (FAO). In the oxidative stressed bone marrow (BM) microenvironment, AML cells are supplied free fatty acids by abundant BM adipocytes, and utilize for FAO. FAO involves a series of reactions to generate acetyl-CoA from fatty acid under aerobic conditions. Acetyl-CoA enters the TCA cycle.

Figure 2

Interactions with adipocytes promotes fatty acid metabolism in AML. BM adipocytes prevent cell death of AML via FAO stimulation, with activation of AMPK and HSP chaperone proteins and modulation of transcription factors in vitro. (A) Fatty acids are obtained from the extracellular microenvironment through lipolysis of stored triglycerides in adipocytes. (B) BM adipocytes induce upregulation of PPARγ, CD36, and FABP4 gene transcription, which stimulates fatty acid endocytosis. The networks of transcriptional regulation and fatty acid metabolism support AML cells in a quiescent state associated with activation of AMPK, p38 with autophagy induction, upregulation of HSP anti-apoptotic chaperone proteins and chemoresistance. (C) In mitochondria, fatty acids are consumed for FAO, resulting in decrease of mitochondrial ROS formation and intracellular oxidative stress. FAO inhibition induces the integrated stress response, which stimulates transcriptional activation of ATF4 and facilitates apoptosis induction by chemotherapeutic drug. FABP4, fatty acid binding protein 4; AMPK, AMP-activated protein kinase; p38, p38 mitogen-activated protein kinase; ADIPOR1, adiponectin receptor 1; ATF4, activating transcription factor 4.