Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells

Abstract

Leukemia cells in the bone marrow (BM) must meet the biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the BM is a novel therapeutic approach. In the present study, we investigated the metabolic role of BM adipocytes in supporting the growth of leukemic blasts. Prevention of nutrient starvation-induced apoptosis of leukemic cells by BM adipocytes, as well as the metabolic and molecular mechanisms involved in this process, were investigated using various analytical techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by BM adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with the upregulation of PPARγ, FABP4, CD36, and BCL2 genes. In AMoL cells, BM adipocyte co-culture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone heat shock proteins. Inhibition of FAO disrupted metabolic homeostasis, increased reactive oxygen species production, induced the integrated stress response mediator ATF4, and apoptosis in AMoL cells co-cultured with BM adipocytes. Our results suggest that BM adipocytes support AMoL cell survival by regulating their metabolic energy balance, and that the disruption of FAO in BM adipocytes may be an alternative, novel therapeutic strategy for AMoL therapy.

Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML

“…These activities has been mediated by adipokines including interleukin-8 (IL-8) along with upregulation of a lipid chaperone FABP4 both in omental metastases ovarian tumors. FABP4 level is also increased in AML cells cultured with BM adipocytes (25), and knockdown of a lipid chaperone FABP4 prolonged survival of a Hoxa9/Meis1-driven murine leukemia model (24). These findings suggest that FABP4 has a key role in cancer cells survival.…”

“…BM adipocytes also increase adiponectin receptor expression as well as its downstream target stress response kinase, AMPactivated protein kinase (AMPK) (25), which is a key modulator of energy metabolism and is activated under conditions of ATP depletion. AMPK exerts long-term metabolic control, including upregulation of fatty acid uptake, FAO, as well as autophagy regulation (32,33).…”

Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

“…Of note, high expression of CD39 was associated with a higher activity resulting in eATP hydrolysis to support AML regrowth and relapse. Bone marrow microenvironment is a key regulator of leukemia growth and has many chemoprotecting effects for AML cells (23,43,44). We and others have shown that mitochondrial OxPHOS is a crucial contributing factor of AML chemoresistance and its inhibition sensitizes cells to AraC treatment (6,7,45).…”

Yellow adipocytes comprise a new adipocyte sub-type present in human bone marrow

“…However, it is unclear whether these differentiated cells recapitulate the phenotype of mature human primary BM-Ad. These in vitro studies suggest a role for BM-Ad in hematopoiesis regulation (Mattiucci et al, 2018; Naveiras et al, 2009), bone remodeling (Hardaway et al, 2015) and cancer progression (Diedrich et al, 2016; Herroon et al, 2013; Liu et al, 2015; Shafat et al, 2017; Tabe et al, 2017). These issues highlight that our knowledge of the physiological phenotype of primary BM-Ad remains limited.…”