title: Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment.
abstract: Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment.
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Manar S
authors.identifier: 0000-0002-3493-9089
authors.initials: MS
authors.lastname: Shafat
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.|German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.|Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohr
authors.affiliation: School of Biological Sciences, and.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
authors.affiliation: School of Biological Sciences, and.|Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Marlein
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Piddock
authors.affiliation: Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.|Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fenech
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Amina
authors.initials: A
authors.lastname: Abdul-Aziz
authors.affiliation: Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.|Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Turner
authors.affiliation: Pilar Research and Education, Cambridge, United Kingdom; and.
authors.forename: Johnathan A
authors.initials: JA
authors.lastname: Watkins
authors.affiliation: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lawes
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.|Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins