Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses
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Jerome Bourgeais1, Nicole Ishac1, Magdalena Medrzycki2, Marie Brachet-Botineau1, Laura Desbourdes1, Valerie Gouilleux-Gruart1,3, Emmanuel Pecnard1, Florence Rouleux-Bonnin1, Emmanuel Gyan1,4, Jorge Domenech1,5, Frederic Mazurier1, Richard Moriggl6, Kevin D. Bunting2, Olivier Herault1,5, Fabrice Gouilleux1
1CNRS UMR 7292, GICC, Université F Rabelais, Tours, France
2Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA
3CHRU de Tours, Laboratoire d’Immunologie, Tours, France
4CHRU de Tours, Service d’Hématologie Clinique et Thérapie Cellulaire, Tours, France
5CHRU de Tours, Service d’Hématologie Biologique, Tours, France
6University of Veterinary Medicine, Medical University of Vienna and Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
Fabrice Gouilleux, email: firstname.lastname@example.org
Keywords: STAT5, Bcr-Abl, chronic myeloid leukemia, oxidative stress, antioxidants
Received: May 23, 2016 Accepted: July 28, 2016 Published: August 22, 2016
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.
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