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

Autor:	Bourgeais J; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Ishac N; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Medrzycki M; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA., Brachet-Botineau M; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Desbourdes L; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Gouilleux-Gruart V; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.; CHRU de Tours, Laboratoire d'Immunologie, Tours, France., Pecnard E; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Rouleux-Bonnin F; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Gyan E; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.; CHRU de Tours, Service d'Hématologie Clinique et Thérapie Cellulaire, Tours, France., Domenech J; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.; CHRU de Tours, Service d'Hématologie Biologique, Tours, France., Mazurier F; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France., Moriggl R; University of Veterinary Medicine, Medical University of Vienna and Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria., Bunting KD; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA., Herault O; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.; CHRU de Tours, Service d'Hématologie Biologique, Tours, France., Gouilleux F; CNRS UMR 7292, GICC, Université F Rabelais, Tours, France.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Jun 27; Vol. 8 (26), pp. 41876-41889.
DOI:	10.18632/oncotarget.11480
Abstrakt:	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.
Databáze:	MEDLINE
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