title: Hypoxia-Like Signatures Induced by BCR-ABL Potentially Alter the Glutamine Uptake for Maintaining Oxidative Phosphorylation.
abstract: The Warburg effect is probably the most prominent metabolic feature of cancer cells, although little is known about the underlying mechanisms and consequences. Here, we set out to study these features in detail in a number of leukemia backgrounds. The transcriptomes of human CB CD34+ cells transduced with various oncogenes, including BCR-ABL, MLL-AF9, FLT3-ITD, NUP98-HOXA9, STAT5A and KRASG12V were analyzed in detail. Our data indicate that in particular BCR-ABL, KRASG12V and STAT5 could impose hypoxic signaling under normoxic conditions. This coincided with an upregulation of glucose importers SLC2A1/3, hexokinases and HIF1 and 2. NMR-based metabolic profiling was performed in CB CD34+ cells transduced with BCR-ABL versus controls, both cultured under normoxia and hypoxia. Lactate and pyruvate levels were increased in BCR-ABL-expressing cells even under normoxia, coinciding with enhanced glutaminolysis which occurred in an HIF1/2-dependent manner. Expression of the glutamine importer SLC1A5 was increased in BCR-ABL+ cells, coinciding with an increased susceptibility to the glutaminase inhibitor BPTES. Oxygen consumption rates also decreased upon BPTES treatment, indicating a glutamine dependency for oxidative phosphorylation. The current study suggests that BCR-ABL-positive cancer cells make use of enhanced glutamine metabolism to maintain TCA cell cycle activity in glycolytic cells.
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Sontakke
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Koczula
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jaques
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Albertus T J
authors.initials: AT
authors.lastname: Wierenga
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Annet Z
authors.initials: AZ
authors.lastname: Brouwers-Vos
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Maurien
authors.initials: M
authors.lastname: Pruis
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ulrich L
authors.initials: UL
authors.lastname: Günther
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jan Jacob
authors.initials: JJ
authors.lastname: Schuringa
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D005973:Glutamine; D016044:Fusion Proteins, bcr-abl