Oncotarget

Research Papers:

Reactive oxygen species levels control NF-κB activation by low dose deferasirox in erythroid progenitors of low risk myelodysplastic syndromes

Mathieu Meunier _, Sarah Ancelet, Christine Lefebvre, Josiane Arnaud, Catherine Garrel, Mylène Pezet, Yan Wang, Patrice Faure, Gautier Szymanski, Nicolas Duployez, Claude Preudhomme, Denis Biard, Benoit Polack, Jean-Yves Cahn, Jean Marc Moulis and Sophie Park

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Oncotarget. 2017; 8:105510-105524. https://doi.org/10.18632/oncotarget.22299

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Abstract

Mathieu Meunier1,2, Sarah Ancelet2, Christine Lefebvre3, Josiane Arnaud4, Catherine Garrel4, Mylène Pezet5, Yan Wang2, Patrice Faure4, Gautier Szymanski3, Nicolas Duployez6, Claude Preudhomme6, Denis Biard7, Benoit Polack2,3, Jean-Yves Cahn1,2, Jean Marc Moulis8,9,10 and Sophie Park1,2

1CHU Grenoble Alpes, University Clinic of Hematology, Grenoble, France

2Université Grenoble Alpes, CNRS UMR 5525, Grenoble INP, CHU Grenoble Alpes, TIMC-IMAG ThEREx, Grenoble, France

3Laboratory of Hematology, CHU Grenoble Alpes, Grenoble, France

4Unité de Biochimie Hormonale et Nutritionnelle, Département de Biologie - Toxicologie - Pharmacologie, CHU Grenoble Alpes, Grenoble, France

5Plateforme de Microscopie Photonique - Cytométrie en Flux, Institut Albert Bonniot, La Tronche, France

6Laboratory of Hematology and Tumor Bank, INSERM UMR-S 1172, Cancer Research Institute of Lille, CHRU of Lille, University Lille Nord de France, Lille, France

7CEA, Institut de Biologie François Jacob, SEPIA, Team Cellular Engineering and Human Syndromes, Université Paris-Saclay, Fontenay-aux-Roses, France

8Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France

9INSERM U1055, Grenoble, France

10CEA-Grenoble, Bioscience and Biotechnology Institute, Grenoble, France

Correspondence to:

Mathieu Meunier, email: mmeunier2@chu-grenoble.fr

Keywords: myelodysplastic syndromes; deferasirox; iron chelation; erythropoiesis; oxidative stress

Received: July 21, 2017     Accepted: August 26, 2017     Published: November 06, 2017

ABSTRACT

Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3μM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-κB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-κB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-κB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents.


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PII: 22299