Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells

Leukemia cells in the bone marrow must meet the biochemical demands of increased cell proliferation and also survive by continually adapting tofluctuations innutrientand oxygen availability. Thus, targetingmetabolic abnormalities in leukemia cells located in the bonemarrow is a novel therapeutic approach. In this study, we investigated the metabolic role of bone marrow adipocytes in supporting the growth of leukemic blasts. Prevention of nutrient starvation-induced apoptosis of leukemic cells by bone marrow adipocytes, as well as the metabolic and molecular mechanisms involved in this process, was investigated using various analytic techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by bonemarrow adipocytes was associated with an increase in fatty acid β -oxidation (FAO) along with the upregulation of PPARg, FABP4, CD36, and BCL2 genes. In AMoL cells, bonemarrow adipocyte coculture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38MAPK with autophagy activation, and upregulated antiapoptotic chaperone HSPs. Inhibition of FAO disruptedmetabolic homeostasis, increased reactive oxygen species production, and induced the integrated stress response mediator ATF4 and apoptosis in AMoL cells cocultured with bone marrow adipocytes. Our results suggest that bone marrow adipocytes support AMoL cell survival by regulating their metabolic energy balance and that the disruption of FAO in bone marrow adipocytes may be an alternative, novel therapeutic strategy for AMoL therapy.