title: The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells.
abstract: The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX-treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self-renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium-sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (β-Catenin) and BMI1. These DFX-mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up-regulation of the erythropoietic marker CD71 (TFRC) and were compound-specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron-chelating property but through ROS signalling activation, may influence key factors involved in self-renewal/differentiation of haematopoietic stem cells.
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Tataranni
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Agriesti
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Mazzoccoli
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.
authors.forename: Vitalba
authors.initials: V
authors.lastname: Ruggieri
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Scrima
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.affiliation: Laboratory of Clinical Research and Advanced Diagnostics, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (PZ), Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: D'Auria
authors.affiliation: Haematology and Clinical Immunology Section, University of Perugia, Perugia, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.affiliation: Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.affiliation: Scientific Direction, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (PZ), Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Centre of Basilicata, Rionero in Vulture (Pz), Italy.|Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D000077588:Deferasirox; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014230:Triazoles; D000077588:Deferasirox
keywords: deferasirox; differentiation; haematopoietic stem cell; myelodysplastic syndromes; reactive oxygen species