STAT5 triggersBCR-ABL1mutation by mediating ROS production in chronic myeloid leukaemia

// Wolfgang Warsch 1,* , Eva Grundschober 1,* , Angelika Berger 1 , Lars Gille 1 , Sabine Cerny-Reiterer 2,3 , Anca-Sarmiza Tigan 1 , Andrea Hoelbl-Kovacic 1 , Peter Valent 2,3 , Richard Moriggl 4 & Veronika Sexl 1 1 Institute of Pharmacology and Toxicology, Veterinary University Vienna, Veterinaerplatz 1, 1210 Vienna, Austria 2 Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna (MUV), Austria 3 Ludwig Boltzmann Cluster Oncology, Vienna, Austria 4 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria * Denotes equal contribution Correspondence: Veronika Sexl, email: // Keywords : BCR-ABL1, Chronic Myeloid Leukaemia, Reactive Oxygen Species, STAT5, mutation Received : December 29, 2012, Accepted : December 31, 2012, Published : December 31, 2012 Abstract We recently reported that chronic myeloid leukaemia (CML) patients harbour high levels of STAT5 when they progress to advanced phases of disease. Advanced disease is characterized by an increased incidence of BCR-ABL1 mutations. We now describe a highly significant correlation between STAT5 expression and the incidence of BCR-ABL1 mutations in primary CML. Forced expression of STAT5 in murine BCR-ABL1 transformed cells sufficed to enhance the production of reactive oxygen species (ROS) and to trigger DNA damage. STAT5-mediated ROS production is independent of JAK2 but requires concomitant BCR-ABL1 signalling as forced STAT5 expression in untransformed BCR-ABL1 negative cells has no impact on ROS levels. Only within the context of a BCR-ABL1 positive cell does STAT5 transcriptionally regulate a target gene or set of genes that causes the enhanced ROS production. Our study suggests the existence of a feed-forward loop accelerating disease progression, in which BCR-ABL1 enhances its own mutation rate in a STAT5-ROS dependent manner. This model explains the increased occurrence of inhibitor-resistant BCR-ABL1 mutations in advanced disease stages driven and characterized by high STAT5 expression.