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

// Mathieu Meunier 1, 2 , Sarah Ancelet 2 , Christine Lefebvre 3 , Josiane Arnaud 4 , Catherine Garrel 4 , Mylene Pezet 5 , Yan Wang 2 , Patrice Faure 4 , Gautier Szymanski 3 , Nicolas Duployez 6 , Claude Preudhomme 6 , Denis Biard 7 , Benoit Polack 2, 3 , Jean-Yves Cahn 1, 2 , Jean Marc Moulis 8, 9, 10 and Sophie Park 1, 2 1 CHU Grenoble Alpes, University Clinic of Hematology, Grenoble, France 2 Universite Grenoble Alpes, CNRS UMR 5525, Grenoble INP, CHU Grenoble Alpes, TIMC-IMAG ThEREx, Grenoble, France 3 Laboratory of Hematology, CHU Grenoble Alpes, Grenoble, France 4 Unite de Biochimie Hormonale et Nutritionnelle, Departement de Biologie - Toxicologie - Pharmacologie, CHU Grenoble Alpes, Grenoble, France 5 Plateforme de Microscopie Photonique - Cytometrie en Flux, Institut Albert Bonniot, La Tronche, France 6 Laboratory of Hematology and Tumor Bank, INSERM UMR-S 1172, Cancer Research Institute of Lille, CHRU of Lille, University Lille Nord de France, Lille, France 7 CEA, Institut de Biologie Francois Jacob, SEPIA, Team Cellular Engineering and Human Syndromes, Universite Paris-Saclay, Fontenay-aux-Roses, France 8 Universite Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France 9 INSERM U1055, Grenoble, France 10 CEA-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.