title: Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses.
abstract: STAT5 transcription factors are frequently activated in hematopoietic neoplasms and are targets of various tyrosine kinase oncogenes. Evidences for a crosstalk between STAT5 and reactive oxygen species (ROS) metabolism have recently emerged but mechanisms involved in STAT5-mediated regulation of ROS still remain elusive. We demonstrate that sustained activation of STAT5 induced by Bcr-Abl in chronic myeloid leukemia (CML) cells promotes ROS production by repressing expression of two antioxidant enzymes, catalase and glutaredoxin-1(Glrx1). Downregulation of catalase and Glrx1 expression was also observed in primary cells from CML patients. Catalase was shown not only to reduce ROS levels but also, to induce quiescence in Bcr-Abl-positive leukemia cells. Furthermore, reduction of STAT5 phosphorylation and upregulation of catalase and Glrx1 were also evidenced in leukemia cells co-cultured with bone marrow stromal cells to mimic a leukemic niche. This caused downregulation of ROS levels and enhancement of leukemic cell quiescence. These data support a role of persistent STAT5 signaling in the regulation of ROS production in myeloid leukemias and highlight the repression of antioxidant defenses as an important regulatory mechanism.
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Jerome
authors: J
authors: Bourgeais
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Nicole
authors: N
authors: Ishac
authors: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA.
authors: Magdalena
authors: M
authors: Medrzycki
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Marie
authors: M
authors: Brachet-Botineau
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Laura
authors: L
authors: Desbourdes
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.|CHRU de Tours, Laboratoire d'Immunologie, Tours, France.
authors: Valerie
authors: V
authors: Gouilleux-Gruart
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Emmanuel
authors: E
authors: Pecnard
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Florence
authors: F
authors: Rouleux-Bonnin
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.|CHRU de Tours, Service d'Hématologie Clinique et Thérapie Cellulaire, Tours, France.
authors: Emmanuel
authors: E
authors: Gyan
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.|CHRU de Tours, Service d'Hématologie Biologique, Tours, France.
authors: Jorge
authors: J
authors: Domenech
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Frederic
authors: F
authors: Mazurier
authors: University of Veterinary Medicine, Medical University of Vienna and Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors: Richard
authors: R
authors: Moriggl
authors: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA.
authors: Kevin D
authors: KD
authors: Bunting
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.|CHRU de Tours, Service d'Hématologie Biologique, Tours, France.
authors: Olivier
authors: O
authors: Herault
authors: CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
authors: Fabrice
authors: F
authors: Gouilleux
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; C516005:GLRX protein, human; D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; D002374:Catalase; D016044:Fusion Proteins, bcr-abl
keywords: Bcr-Abl; STAT5; antioxidants; chronic myeloid leukemia; oxidative stress