Oxidative stress and mitochondrial dysfunction play a role in myelodysplastic syndrome development, diagnosis, and prognosis: A pilot study

Abstract

The imbalance between reactive oxygen species (ROS) production and their elimination by antioxidants leads to oxidative stress. Depending on their concentration, ROS can trigger apoptosis or stimulate cell proliferation. We hypothesized that oxidative stress and mitochondrial dysfunction may participate not only in apoptosis detected in some myelodysplastic syndrome (MDS) patients, but also in increasing proliferation in other patients. We investigated the involvement of oxidative stress and mitochondrial dysfunction in MDS pathogenesis, as well as assessed their diagnostic and prognostic values. Intracellular peroxides, superoxide, superoxide/peroxides ratio, reduced glutathione (GSH), and mitochondrial membrane potential (Δψ(mit)) levels were analyzed in bone marrow cells from 27 MDS patients and 12 controls, by flow cytometry. We observed that all bone marrow cell types from MDS patients had increased intracellular peroxide levels and decreased GSH content, compared with control cells. Moreover, oxidative stress levels were MDS subtype- and risk group-dependent. Low-risk patients had the highest ROS levels, which can be related with their high apoptosis; and intermediate-2-risk patients had high Δψ(mit) that may be associated with their proliferative potential. GSH levels were negatively correlated with transfusion dependency, and peroxide levels were positively correlated with serum ferritin level. GSH content proved to be an accurate parameter to discriminate patients from controls. Finally, patients with high ROS or low GSH levels, as well as high superoxide/peroxides ratio had lower overall survival. Our results suggest that oxidative stress and mitochondrial dysfunction are involved in MDS development, and that oxidative stress parameters may constitute novel diagnosis and/or prognosis biomarkers for MDS.

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

“…In this study, BM cells from MDS patients showed an increased level of intracellular ROS in comparison with healthy donors. Our results, in agreement with previous studies (Ghoti et al , ; Novotna et al , ; Saigo et al , ; Gonçalves et al , ) would support the idea that MDS cells are subjected to oxidative stress. Intriguingly, lymphoid cells consistently presented lower levels of ROS than myeloid cells, in both patients and controls.…”

Correlation of Oxidative Stress Biomarkers and Hematological Parameters in Blood Cancer Patients from Sardinia, Italy

“…Regarding MDS patients, Pimkova et al 23 did not observe increased MDA levels which contrasts with our findings in this group of patients. But, Goncalves et al 16 in agreement with our study observed increased ROS levels and consequently the involvement of oxidative stress to the development of MDS. Among all the analyzed hematological malignancies, we found an increase of oxidative damage, although of varying degrees.…”

“…Among them, myelodysplastic syndromes (MDS) represent a unique scenario as oxidative stress can increase due to both transfusion-dependent iron overload and dyserythropoiesis itself. 16 Publications from different groups have presented measurements of different oxidative stress biomarkers for different hematological malignancies such as acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL) and Myelodysplastic syndromes [17][18][19][20][21][22][23] . Battisti et al measured plasmatic thiobarbituric acid-reactive substances (TBARS), serum protein carbonylation, whole blood catalase (CAT) and superoxide dismutase (SOD) activities in ALL patients 22 .…”

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis

“…The oxidative stress has been implicated in the pathogenesis and prognosis of MDS . This cellular state is modulated by antioxidant and base excision repair enzymes, such as superoxide dismutase (SOD) and 8‐oxoguanine DNA glycosylase (OGG1), respectively, as well as by transcriptional factors, such as nuclear factor erythroid 2‐like 2 (NRF2) .…”