Iron overload-induced oxidative stress in myelodysplastic syndromes and its cellular sequelae

Abbreviations: 4-HNE, 4-hydroxy-2-nonenol; 8-OH-dG, 8-hydroxy-2 '-deoxyguanosine; 8-iso-PGF-2a, 8-iso-prostaglandin 2 alpha; AML, Acute myeloid leukemia; AMP, Adenosine monophosphate; ARNT, Aryl hydrocarbon receptor nuclear translocator; ATM, Ataxia telangiectasia mutated gene; ATP, Adenosine triphosphate; BER, Base excision repair; BFU-E, Burst forming unit - erythroid; BME, Bone marrow microenvironment; BTM, Beta thalassemia major; CBP, Creb binding protein; CD, Cluster of differentiation; CFOS, Cellular FBJ (Finkel-Biskis-Jinkins) Murine Osteosarcoma; CFU-GM, Colony forming unit - Granulocyte Macrophage; CFU-megaE, Colony forming unit - Megakaryocyte Erythrocyte; CFU-Mix, Colony forming unit multipotent; CREB, cAMP response element binding protein; CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C Chemokine Receptor 4; Cys, Cysteine; DA, Diacetate; DCF, Dichlorohydrofluorescein; DDT, Dichlorodiphenyltrichloroethane; DFO, Deferoxamine; DFP, Deferiprone; DFS, Disease-free survival; DFX, deferasirox; DHE, Dihydroethidium; DMT1, Divalent metal transporter 1; DNA, Deoxyribonucleic acid; DNPH, 2,4-dinitrophenylhydrazine; d-ROMS, Diacron reactive oxygen metabolites; DSB, Double strand breaks; E2F1, E2F Transcription Factor 1; EFS, Event-free survival; ELISA, Enzyme linked immunosorbent assay; eLPI, Enhanced labile plasma iron; EPIC, Evaluation of Patients' Iron Chelation with Exjade ((R)); ER, Endoplasmic reticulum; ERO, Endoplasmic reticulum oxidoreductin; ETC, Electron transport chain; EUMDS, European LeukemiaNet MDS registry; FOX, Ferrous oxidation xylenol orange; FOXO, Forkhead/winged helix box gene group O; G6PD, Glucose-6-phosphate dehydrogenase; GADPH, Glyceraldehyde 3-phosphate dehydrogenase; GCS, gamma-glutamyl cysteine synthetase; GGNER, Genome nucleotide excision repair; GI, Gastrointestinal; GLUD, Glutamate dehydrogenase; GLUL, Glutamine synthetase; GM-CSFR, Granulocyte-macrophage colony-stimulating factor receptor; GPX, Glutathione peroxidase; GRIM, Genes associated with the retinoid-interferon-induced mortality; H-, Heavy; H2O2, Hydrogen peroxide; HFE, Hereditary hemochromatosis; HI, Hematologic improvement; HIF-1 alpha, Hypoxiainducible factor 1 alpha; HIF-1b, Hypoxia-inducible factor 1 beta; HMA, Hypomethylating agents; HOCl, Hypochlorous acid; HOX, Homeobox protein; HPC, Hematopoietic progenitor cell; HPLC, High performance liquid chromatography; HSC, Hematopoietic stem cell; HSCT, Hematopoietic stem cell transplant; ICT, Iron chelation therapy; IGF, Insulin-like growth factor; IHC, Immunohistochemistry; IOL, Iron overload; IPSS, International Prognostic Scoring System; IRE, Iron response element; IRP, Iron response protein; KIT, KIT Proto-Oncogene, Receptor Tyrosine Kinase; KO, Knockout; L-, Light; LDL, Low density lipoprotein; LFS, Leukemia-free The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.

Automated summary

Iron overload-induced reactive oxygen species affect cellular activities, leading to dysfunction in hematopoietic stem cells and other cells, exacerbating the pathophysiology of myelodysplastic syndromes.