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 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.
Highlights
The Signal Transducer and Activator of Transcription factors 5A and 5B are two closely related STAT family members that play a major role in normal and leukemic hematopoiesis [1]
To determine whether STAT5 activation is involved in reactive oxygen species (ROS) production, we examined the functional consequence of STAT5 inhibition on the regulation of ROS levels in Bcr-Abl+ cells
Oxidative stress has been found in many cancers, including hematologic malignancies and elevated ROS levels have been detected in hematopoietic cells transformed by JAK2V617F, FLT3-ITD and Bcr-Abl oncogenes [21,22,23]
Summary
The Signal Transducer and Activator of Transcription factors 5A and 5B are two closely related STAT family members that play a major role in normal and leukemic hematopoiesis [1]. Previous reports indicated that STAT5 is a direct target of these TKOs, but additional events linked to cell transformation are probably involved in STAT5 activation [12, 13] It was shown, for instance, that ROS, which are generated in oncogene-transformed cells regulate different redox-sensitive signaling pathways by inducing the reversible oxidation of tyrosine phosphatases, protein kinases and transcription factors [14, 15]. We show that oncogenic activation of STAT5 induced by Bcr-Abl in CML cells enhances ROS levels through the repression of catalase and glutaredoxin-1 (Glrx1), two enzymes involved in antioxidant defenses These data suggest that deregulated STAT5 activity directly affects the balance between ROS generation and scavenging to promote oxidative stress in myeloid leukemias
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