Oxidative imbalance in low/intermediate-1-risk myelodysplastic syndrome patients: The influence of iron overload

Ivars, David; Orero, Maite; Javier, Karla; Díaz-Vico, Laura; García-Giménez, José Luis; Mena, Salvador; Tormos, Carmen; Egea, Mercedes; Pérez, Pedro Luis Hernández; Arrizabalaga, Beatriz; Ruiz, María Ángeles; Yagüe, Nuria; Tormo, Mar; Sancho-Tello, Reyes; Gomes, Ana Julia Pereira Santinho; Algueró, Carmen; O’Connor, José-Enrique; Sáez, Guillermo T.; Carbonell, Félix; Collado, Rosa

doi:10.1016/j.clinbiochem.2017.05.018

Cited by 18 publications

(21 citation statements)

References 37 publications

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“…Myelodysplastic syndrome is a heterogeneous group of clonal stem cell disorders characterized by multilineage dysplasia, ineffective hematopoiesis, pancytopenia, and with a high risk of developing into acute myeloid leukemia. 18 Over recent years, investigators all over the world have been trying hard to establish an MDS model to further study this disease. However, only a few mouse models are available for human MDS.…”

Section: Discussionmentioning

confidence: 99%

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Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Jin

Cao

et al. 2018

Haematologica

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There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the RUNX1S291fs-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.

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Section: Discussionmentioning

confidence: 99%

“…In addition, our mice can be used to illustrate the association between oxidative imbalance and iron overload in MDS. 18 Our previous study showed that damaged mesenchymal stromal cells (MSC) were related to iron overload induced ROS in normal mice. 21 However, Zheng et al .…”

Section: Discussionmentioning

confidence: 99%

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Jin

Cao

et al. 2018

Haematologica

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“…However, avoiding the generation of oxidative stress in MDS patients could be a more effective strategy. If we assume that iron overload is involved in the induction of oxidative stress in MDS patients (Ivars et al , ), it could be surmised that treatments devoted to reducing iron overload could also be beneficial in terms of lowering the oxidative stress. Some studies seem to support this notion: it has been shown that in vitro treatment with iron chelators or antioxidants ameliorates the oxidative stress in peripheral blood cells from MDS patients (Ghoti et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, iron can act as a catalyst in Fenton and Haber‐Weiss reactions (Graf et al , ) producing ROS. Therefore, iron overload could induce a situation of oxidative stress in MDS patients (Ivars et al , ). Consequently, it is reasonable to suggest that oxidative stress could play a role in MDS aetiology and in its progression towards AML (Pilo & Angelucci, ).…”

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confidence: 99%

Deferasirox reduces oxidative DNA damage in bone marrow cells from myelodysplastic patients and improves their differentiation capacity

et al. 2019

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Patients with low-risk myelodysplastic syndromes (MDS) usually develop iron overload. This leads to a high level of oxidative stress in the bone marrow (BM) and increases haematopoietic cell dysfunction. Our objective was to analyse whether chelation with deferasirox (DFX) alleviates the consequences of oxidative stress and improves BM cell functionality. We analysed 13 iron-overloaded MDS patients' samples before and 4-10 months after treatment with DFX. Using multiparametric flow cytometry analysis, we measured intracellular reactive oxygen species (ROS), DNA oxidation and double strand breaks. Haematopoietic differentiation capacity was analysed by colony-forming unit (CFU) assays. Compared to healthy donors, MDS showed a higher level of intracellular ROS and DNA oxidative damage in BM cells. DNA oxidative damage decreased following DFX treatment. Furthermore, the clonogenic assays carried out before treatment suggest an impaired haematopoietic differentiation. DFX seems to improve this capacity, as illustrated by a decreased cluster/CFU ratio, which reached values similar to controls. We conclude that BM cells from MDS are subject to higher oxidative stress conditions and show an impaired haematopoietic differentiation. These adverse features seem to be partially rectified after DFX treatment.The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant haematopoietic stem cell disorders that result in clonal haematopoiesis. This disorder occurs with cytopenia and dysplastic features as a consequence of ineffective haematopoiesis. Clinical presentation and evolution of MDS is heterogeneous. Anaemic syndrome, increased risk of infections and haemorrhagic manifestations are often present. These clinical aspects vary depending on the predominant cytopenia in each case, with anaemia being the most prevalent (up to 80-90% of patients) and the major

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“…In a recent study on neutrophils from 42 MDS patient samples with or without iron overload, the 14 patients with a ferritin level higher than 1000 µg/l, or more than 70% transferrin saturation, had a higher detectable 0 2 . ‐ and glutathione, detected by flow cytometry (Ivars et al , ). In turn, this excessive production of oxygen radicals contributes to organ damage, with hepatic and cardiac morbidity secondary to iron overload (de Montalembert et al , ), and may also impair haematopoiesis by increasing DNA instability.…”

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confidence: 99%

Less iron improves MDS haematopoiesis

Gyan

Almeida

2019

Br J Haematol

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Oxidative imbalance in low/intermediate-1-risk myelodysplastic syndrome patients: The influence of iron overload

Cited by 18 publications

References 37 publications

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Deferasirox reduces oxidative DNA damage in bone marrow cells from myelodysplastic patients and improves their differentiation capacity

Less iron improves MDS haematopoiesis

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