title: Metabolic plasticity in CLL: adaptation to the hypoxic niche.
abstract: Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1α) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the 'primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Koczula
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Ludwig
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hayden
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: L
authors.initials: L
authors.lastname: Cronin
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.|Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK.
authors.forename: G
authors.initials: G
authors.lastname: Pratt
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: H
authors.initials: H
authors.lastname: Parry
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: D
authors.initials: D
authors.lastname: Tennant
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Drayson
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Bunce
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: F L
authors.initials: FL
authors.lastname: Khanim
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: U L
authors.initials: UL
authors.lastname: Günther
mesh_terms: D000222:Adaptation, Physiological; D059447:Cell Cycle Checkpoints; D015687:Cell Hypoxia; D002952:Citric Acid Cycle; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D019289:Pyruvic Acid / Q000494:pharmacology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019289:Pyruvic Acid