title: 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 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 bone marrow 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 bone marrow adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with the upregulation ofPPARγ, FABP4, CD36, andBCL2genes. In AMoL cells, bone marrow adipocyte coculture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone HSPs. Inhibition of FAO disrupted metabolic 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.Cancer Res; 77(6); 1453-64. ©2017 AACR.
authors.affiliation: Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.|Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Next Generation Hematology Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.|Leading Center for the Development and Research of Cancer Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Saitoh
authors.affiliation: Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Sekihara
authors.affiliation: Center for Information Biology, National Institute of Genetics, Sizuoka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Monma
authors.affiliation: Center for Information Biology, National Institute of Genetics, Sizuoka, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Ikeo
authors.affiliation: Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Hematology, Aichi Medical University, Aichi, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shikami
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jo
authors.initials: J
authors.lastname: Ishizawa
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.affiliation: Division of Proteomics and BioMolecular Science, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Saiko
authors.initials: S
authors.lastname: Kazuno
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Preventive Medicine and Diagnosis Innovation Program, RIKEN, Kanagawa, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Yamanaka
authors.affiliation: Division of Proteomics and BioMolecular Science, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nagaoka
authors.affiliation: Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.affiliation: Preventive Medicine and Diagnosis Innovation Program, RIKEN, Kanagawa, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D018920:Coculture Techniques; D005227:Fatty Acids / Q000737:chemistry*; D053263:Gene Regulatory Networks; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000378:metabolism / Q000473:pathology*; D050356:Lipid Metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases