Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses

• Type of Material: Article
• Authors: Jerome Bourgeais, Université F Rabelais; Nicole Ishac, Université F Rabelais; Magdalena Medrzycki, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta; Marie Brachet-Botineau, Université F Rabelais; Laura Desbourdes, Université F Rabelais; Valerie Gouilleux-Gruart, Université F Rabelais; Emmanuel Pecnard, Université F Rabelais; Florence Rouleux-Bonnin, Université F Rabelais; Emmanuel Gyan, Université F Rabelais; Jorge Domenech, Université F Rabelais; Frederic Mazurier, Université F Rabelais; Richard Moriggl, Medical University of Viennaand Ludwig Boltzmann Institute for Cancer Research; Kevin Bunting, Emory University; Olivier Herault, Université F Rabelais; Fabrice Gouilleux, Université F Rabelais
• Language: English
• Date: 2017-06-27
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © Bourgeais et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.11480
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 8
• Issue: 26
• Start Page: 41876
• End Page: 41889
• Grant/Funding Information: JB was supported by CNRS, Conseil Regional Centre and Ligue Contre le Cancer (Comité Indre et Loire).; RM was supported by grants SFB-F28 and SFB-F47 from the Austrian Science Fund (FWF).; This study was supported by Conseil Regional Centre, Ligue Contre le Cancer interregional Grand Ouest, CANCEN society, “Sapin de l’Espoir Contre le Cancer”, International Rotary (Club of Blois), Federative Programme FHU GOAL.
• Keywords: ROS PRODUCTION; POLYCYTHEMIA-VERA; REDOX REGULATION; CATALASE; TRANSFORMATION; Bcr-Abl; HEMATOPOIETIC STEM-CELLS; Science & Technology; STAT5; THERAPEUTIC OPPORTUNITIES; oxidative stress; Life Sciences & Biomedicine; STEM/PROGENITOR CELLS; Cell Biology; chronic myeloid leukemia; GENOMIC INSTABILITY; CONSTITUTIVE ACTIVATION; antioxidants; Oncology
• Research Categories: Health Sciences, General

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 cocultured 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.