Journal
ONCOTARGET
Volume 8, Issue 62, Pages 105510-105524Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22299
Keywords
myelodysplastic syndromes; deferasirox; iron chelation; erythropoiesis; oxidative stress
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Funding
- Novartis
- Universite Joseph Fourier Grenoble (Programme AGIR)
- Bourse Espoir Sandrine
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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 (3 mu M), 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-kappa B pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-kappa B modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-kappa B. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents.
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