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.

Active fatty acid oxidation defines the cellular response towards reactive oxygen species

“…(Cheng et al, 2020; Kajihara et al, 2017; Lee and Paull, 2020; Xie et al, 2020) As a matter of fact, involvement of FAO as protective mechanism against ROS, is a quite well-known concept in cancer cells, resulting in new approaches for tumour therapy. (Pike et al, 2011; Stoykova and Schlaepfer, 2019; Tabe et al, 2020) To our knowledge, the relation between distinctive responses to ROS-inducing xenobiotics and active FAO in healthy tissues surprisingly only receives little attention. As we could demonstrate, that FAO activity is the underlying cause for strongly differing effects of DEHP on hematopoietic lineages, we recommend that future toxicological studies should also address initial metabolic fluxes in their experimental systems.…”

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

“…This is found in ROS-low LSCs and those isolated from relapsed AML samples. 332,341 LSCs and AML bulk cells that reside in the BM stimulate BM adipocytes to generate fatty acids through lipolysis. This promotes the salvage of these adipocyte-produced fatty acids by LSCs to generate intermediates for the TCA cycle and OXPHOS.…”

“… 332 In fact, it is well documented that LSCs are supported by adipocytes in the BM microenvironment to supply lipids for fatty acid oxidation (FAO). 341 Therefore, treating AML and eradicating LSCs early on during treatment is essential to avoid altered metabolic homeostasis in this small cell subpopulation. So far, elucidating the molecular mechanisms regulating metabolic homeostasis of LSCs has illuminated strategies for novel targeted therapeutics for the treatment of AML.…”

Adipogenesis in Different Body Depots and Tumor Development

“…Adipokines and free fatty acids released by BM adipocytes directly or indirectly interfere with cells of bone remodeling or hematopoiesis (Hardouin et al, 2016). Tumor cells can induce the phosphorylation of hormone-sensitive lipase and activate lipolysis in BMAT, allowing the transfer of fatty acids from adipocytes to tumor cells in AML (Shafat et al, 2017;Tabe et al, 2020), multiple myeloma (Morris et al, 2020), and prostate tumor (Herroon et al, 2019). Importantly, after chemotherapy, marrow necrosis and the loss of myeloid tissue may result in a BMAT expansion (Hwang and Panicek, 2007;Costa and Reagan, 2019), which might create a favorable niche for tumor cells.…”