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

Bourgeais, Jérôme; Ishac, Nicole; Medrzycki, Magdalena; Brachet-Botineau, Marie; Desbourdes, Laura; Gouilleux-Gruart, Valérie; Pecnard, Emmanuel; Rouleux‐Bonnin, Florence; Gyan, Emmanuel; Domenech, Jorge; Mazurier, Frédéric; Moriggl, Richard; Bunting, Kevin D.; Hérault, Olivier; Gouilleux, Fabrice

doi:10.18632/oncotarget.11480

Cited by 34 publications

(27 citation statements)

References 49 publications

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“…In mice, lack of SOD1, Cat, or Hmox1 worsens the diabetic tissue injury by enhancing oxidative stress, while transgenic expression is renoprotective and retards cardiovascular disease [45][46][47]. Furthermore, sustained activation of STATs in leukemia cells represses antioxidant gene expression [48], whereas either hepatic deletion of JAK2 or SOCS1 overexpression in lymphocytes protect against oxidative damage by increasing detoxifying enzymes [49,50]. In agreement, our findings evidence the antioxidant properties of SOCS1-mediated JAK/STAT inhibition through a coordinated cytoprotective response to restore redox balance, although additional studies are needed to delineate the detail mechanism underlying this process.…”

Section: Discussionmentioning

confidence: 99%

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

López-Sanz

Bernal

Recio

et al. 2018

Laboratory Investigation

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Oxidative stress resulting from excessive production of reactive oxygen species (ROS) or impaired antioxidant defenses is closely related to the development of diabetic vascular complications, including nephropathy and atherosclerosis. Chronic activation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes to diabetic complications by inducing expression of genes involved in cell proliferation, fibrosis, inflammation, and oxidative stress. Suppressors of cytokine signaling (SOCS) family of endogenous JAK/STAT regulators is an attractive target for therapeutic intervention. We investigated the beneficial effect of two different SOCS1-targeted therapies (adenovirus-mediated gene transfer and kinase-inhibitory region peptidomimetic) to combat oxidative stress injury in an experimental diabetes model of concomitant renal and macrovascular disease (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Diabetes resulted in progressive alteration of redox balance in mice, as demonstrated by increased ROS levels and decreased antioxidant activity, which ultimately led to renal dysfunction and vascular injury. The molecular and pathological alterations in early diabetes were partially reversed by preventive intervention with SOCS1-targeted therapies. Importantly, SOCS1 peptidomimetic provided reno- and atheroprotection in diabetic mice even in a setting of established disease. Compared with untreated controls, kidney and aorta from SOCS1-treated mice exhibited significantly lower levels of superoxide anion, DNA oxidation marker and NADPH oxidase (Nox) subunits, along with higher expression of antioxidant enzymes. These trends correlated with a reduction in parameters of renal damage (albuminuria, creatinine and tubular injury), atherosclerosis (lesion size) and inflammation (leukocytes and chemokines). Mechanistic studies in renal, vascular and phagocytic cells exposed to cytokines and high-glucose showed that SOCS1 blocked ROS generation by inhibiting both Nox complex assembly and Nox subunit expression, an effect mediated by inactivation of JAK2, STAT1, and PI3K signaling pathways. This study provides evidence for SOCS1-targeted therapies, especially SOCS1 peptidomimetic, as an alternative antioxidant strategy to limit the progression of diabetic micro- and macrovascular complications.

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Section: Discussionmentioning

confidence: 99%

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

López-Sanz

Bernal

Recio

et al. 2018

Laboratory Investigation

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“…In this context, it is of mechanistic interest to link JAK and STAT3/5 activation to regulation of reactive oxygen species (ROS) generation, which is known to cause DNA damage, promoting mutations, oxidization of lipids, or silencing of phosphatases by catalytic cysteine oxidization [113–116]. Surprisingly, wild-type JAK2 decreases detoxifying glutathione S-transferases in epithelial cells, enhancing oxidative damage.…”

Section: Targets In Ptcl and Driver Mutationsmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…The mutator phenotype of BCR-ABL-expressing cells has been also attributed to increased reactive oxygen species (ROS) production. BCR-ABL not only enhances ROS production [55,61,62], but it also promotes oxidative stress in CML cells by repressing antioxidant defenses [63]. Elevated ROS are known to modulate activities of signaling pathways involved in malignant proliferation and apoptosis, such as phosphoinositide 3-kinase/protein kinase B (PI3K/PKB) and mitogen-activated protein kinase (MAPK) signaling pathways through oxidation of negative feedback loop regulators [64][65][66].…”

Section: Role Of Ddr In CML and Pvmentioning

confidence: 99%

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

Stetka

Gurský

Velasquez

et al. 2020

Cancers

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Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions.CML is characterized by an indolent, chronic phase (CP) preceding an acute transformation to BC. Failure of DNA damage repair and loss or malfunction of DDR components accompanied by accumulation of DNA damage and genomic instability has been considered in CML evolution [38,39]. It was proposed that BCR-ABL-expressing cells feature reduced activation of the ATR-Chk1-mediated DDR signaling, with ensuing accumulation of substantial genomic instability due to replication stress and oxidative damage. Mechanistically, such disruption of ATR-dependent signaling was attributed to nuclear import of BCR-ABL after DNA damage and its binding to ATR [40]. However, contrasting data were also reported, showing that BCR-ABL does activate ATR-Chk1 signaling, reflecting responsiveness of BCR-ABL-positive myeloid cells to DNA damage following genotoxic treatment [41]. Some studies also addressed functionality of the ATM-Chk2 signaling axis in CML. Thus, c-Abl is a nuclear tyrosine kinase activated by DNA damage in an ATM-dependent manner [42,43]. Even though the BCR-ABL is predominantly localized to the cytoplasm [44], the aforementioned ability of BCR-ABL translocation to the nucleus after DNA damage led to a proposal that BCR-ABL and c-Abl share multiple protein interactions including that with ATM [40]. As a consequence, ATM-mediated activatory phosphorylation of Chk2 was detected in BCR-ABL-expressing cellular models and...

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

Cited by 34 publications

References 49 publications

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

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