title: Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche.
abstract: Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36(+) LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA; Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Haobin
authors.initials: H
authors.lastname: Ye
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Biniam
authors.initials: B
authors.lastname: Adane
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Nabilah
authors.initials: N
authors.lastname: Khan
authors.affiliation: Cardiovascular Pulmonary Research Lab, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Minhajuddin
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Gasparetto
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Stevens
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pei
authors.affiliation: Functional Genomics Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.affiliation: Functional Genomics Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Ashton
authors.affiliation: Cardiovascular Pulmonary Research Lab, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Carolien M
authors.initials: CM
authors.lastname: Woolthuis
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alec W
authors.initials: AW
authors.lastname: Stranahan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA. Electronic address: craig.jordan@ucdenver.edu.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
mesh_terms: D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006066:Gonads / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D008066:Lipolysis / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018955:CD36 Antigens; D005227:Fatty Acids