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

Jerome Bourgeais (1) , Nicole Ishac (1) , Magdalena Medrzycki , Marie Brachet-Botineau (1) , Laura Desbourdes (1) , Valérie Gouilleux-Gruart (2) , Emmanuel Pecnard (1) , Florence Rouleux-Bonnin (1) , Emmanuel Gyan (3, 1) , Jorge Domenech (1) , Frédéric Mazurier (1) , Richard Moriggl (4) , Kevin Bunting , Olivier Herault (1) , Fabrice Gouilleux (1)

1 GICC UMR 7292 CNRS - Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017]
2 Développement normal et pathologique des lymphocytes et signalisation
3 Service d'hématologie
4 Medizinische Universität Wien = Medical University of Vienna

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.

Domains: Life Sciences [q-bio]; Cancer; Life Sciences [q-bio]; Human health and pathology; Hematology; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Genomics [q-bio.GN]

Jerome Bourgeais, Nicole Ishac, Magdalena Medrzycki, Marie Brachet-Botineau, Laura Desbourdes, et al.. Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses. Oncotarget, 2017, 8 (26), pp.41876-41889. ⟨10.18632/oncotarget.11480⟩. ⟨hal-02411729⟩