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

https://doi.org/10.1016/j.critrevonc.2021.103367Get rights and content

Highlights

Abstract

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.

Introduction

The myelodysplastic syndromes (MDS) are clonal bone marrow failure disorders characterized by progressive peripheral blood cytopenias and a risk of progression to acute myeloid leukemia (AML) (Fenaux et al., 2020a; Greenberg et al., 1997, 2012). MDS patients often require red blood cell (RBC) transfusions for anemia, resulting in iron overload (IOL), well described in congenital anemias to lead to organ toxicity (Olivieri et al., 1994). By Fenton chemistry, IOL increases production of reactive oxygen species (ROS), oxygen free radicals which can alter cells and macromolecules (Gattermann and Rachmilewitz, 2011; Leitch and Gattermann, 2019; Nathan, 2003; Nathan and Cunningham-Bussel, 2013). Here we illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology, including organ toxicity, cytopenia progression, and AML transformation.

Iron is essential for multiple aspects of cellular metabolism, but the body has no mechanism to excrete an excess. Iron equilibrates between the ferrous (Fe2+) and ferric (Fe3+) states. Excess iron is stored in macrophages and hepatocytes as ferritin or hemosiderin. The serum ferritin (SF) level approximates body iron stores, and despite fluctuations is currently the most convenient measure of iron in clinical practice (Leitch et al., 2018). Most iron is in hemoglobin; it is also present in multiple enzymes (Kohgo et al., 2008; Leitch et al., 2019; Muckenthaler et al., 2017).

Normally, an equivalent amount of iron per day is absorbed from the gastrointestinal (GI) tract, and lost by turnover of epithelial cells. GI absorption is downregulated by hepcidin, while erythropoietic demand for iron is signaled by erythroferrone from erythroblasts (Kohgo et al., 2008; Leitch et al., 2019; Muckenthaler et al., 2017).

Iron is transported by transferrin (Tf) to cells expressing the transferrin receptor (TfR1; TfR2 is present in hepatocytes). The diferric/holo-Tf-TfR complex is taken up by endocytosis, and iron released and transported to the cytoplasm. Regulation of TfR1 and ferritin synthesis are controlled by iron response elements (IREs) on their RNA that bind iron regulatory proteins (IRPs)-1 and -2, which control their translation. Cellular ferritin stores iron as redox inactive and insoluble (Kohgo et al., 2008; Leitch et al., 2019; Muckenthaler et al., 2017). A pool of cellular labile iron is maintained (labile cellular iron; LCI). Most cells have no mechanism for iron efflux. Causes of IOL in acquired anemias include blood transfusions and ineffective erythropoiesis, as hepcidin suppression increases iron absorption (Kohgo et al., 2008).

Increasing evidence suggests that iron is central to multiple disorders. Hereditary hemochromatosis (HFE) heterozygotes are at increased risk of heart disease and stroke. (Hanson et al., 2001; Tuomainen et al., 1999; Munoz-Bravo et al., 2013). Ferritin and Tf saturation predict dysfunctional glucose metabolism and diabetes risk, and are associated with an increase in malignancies and cancer-related deaths (Tuomainen et al., 1999; Ford and Cogswell, 1999; Ellervik et al., 2011; Bonfils et al., 2015; Stevens et al., 1986, 1988; Merk et al., 1990; Knekt et al., 1994; Nelson et al., 1995; Weinberg and Miklossy, 2008).

Due to a high oxygen requirement, more free radicals are produced in the brain (Lee et al., 2007). Increased brain iron deposition is seen in Alzheimer’s, which promotes aggregation of amyloid-b of Alzheimer’s plaques, which in turn generates oxygen radicals; oxidative damage is present in early stages (Lhermitte et al., 1924; Goodman, 1953; Bartzokis et al., 1994; Mantyh et al., 1993; Smith et al., 1997; Nunomura et al., 2001; Smith et al., 2010).

IOL reduction by serial phlebotomy improved insulin sensitivity and glucose metabolism and decreased the likelihood of developing and dying from cancer (Facchini, 1998; Fernandez-Real et al., 2005; Gabrielsen et al., 2012; Kato et al., 2007; Zacharski et al., 2008). Alzheimer’s patients receiving ICT had half the rate of cognitive decline (Crapper McLachlan et al., 1991).

Iron is present in all known life forms. Evidence indicates that iron was involved in signaling billions of years before the existence of adenosine triphosphate (ATP); an electrochemical gradient around hydrothermal vents in the ocean crust served as an energy source to fuel the formation of organic molecules, plasma membranes and cells (Ghose, 2013). Iron induced oxidative species still function in cellular signaling and regulation, discussed further in the following sections.

ROS production is explained in the article “Iron is the new cholesterol” (Dalton, 2018). “Electrons flowing toward oxygen create an energy gradient. Normal metabolism produces low levels of toxic byproducts including the oxygen derivative superoxide. Cells have enzymes that convert most superoxide to hydrogen peroxide, which is detoxified to water and oxygen. If either superoxide or hydrogen peroxide encounter iron, chemical reactions produce a potent and reactive oxygen derivative, the hydroxyl radical, which damages biological molecules.” (Dalton, 2018)

Chemical reactions resulting in ROS production are shown in Fig. 1. Table 1 shows oxidative species formed and their properties. Superoxide and hydroxyl radicals are strongly oxidizing, have a short half-life and are not membrane permeable. Hydrogen peroxide is weakly oxidizing, but has a long half-life and is membrane permeable, and therefore may have an impact on cellular metabolism at a distance.

Pre-clinical studies indicate that ROS damage macromolecules, leading to cellular endpoints (reviewed in (Gattermann and Rachmilewitz, 2011)). Hydroxyl radicals are unstable and react with DNA, proteins and lipids. Effects on DNA include strand breaks and modifications that can cause mutations or cytotoxicity. Mitochondrial DNA (mtDNA) lacks histones for protection and effective DNA repair mechanisms, making it particularly susceptible to oxidative damage. Protein reactions result in cross linking and structural distortions, affecting the function of enzymes, channels and receptors. Lipid peroxidation alters the fluidity and structure of membranes, leading to dysfunction and lysis of cells or organelles. Oxidative damage in mitochondria affects cellular energy production. Free radical reaction with lysosomal membranes can result in organelle rupture, releasing catabolic enzymes, reactive species and free iron into the cytoplasm (Iron Health Alliance, 2014). Changes to macromolecules and their potential relevance to MDS are discussed further below.

MDS are a group of clonal bone marrow disorders. Classification is currently by the World Health Organization (WHO) system (Vardiman, 2010; Strupp et al., 2017). Prognostic scoring systems estimate survival and AML risk; among the most widely used are the International Prognostic Scoring System (IPSS) and its revision, the IPSS-R (Greenberg et al., 1997, 2012). Higher risk groups have progressively decreasing life expectancy and increasing risk of AML transformation. The adverse impact on prognosis of RBC transfusion dependence (TD) is incorporated into the WHO-based Prognostic Scoring System (WPSS) (Malcovati et al., 2007).

MDS incidence increases with age, with the median age of onset in the seventh decade (Ma et al., 2007). Though new treatments are available for subgroups of MDS patients, the mainstay of care for most remains supportive care (Fenaux et al., 2020a; Platzbecker, 2019; Hellstrom-Lindberg, 2005; Fenaux et al., 2011, 2020b; Fenaux et al., 2010; Cutler et al., 2004). A frequently encountered clinical problem is anemia, treated with specific therapies when possible (Hellstrom-Lindberg, 2010; Greenberg et al., 2017). Most patients eventually require RBC transfusion and without intervention, transfusional IOL is inevitable (Balducci, 2006).

Clinical data in MDS generally evaluate IOL toxicity in terms of organ damage, overall survival (OS), leukemia-free survival (LFS) and infection risk; cytopenia progression is likely also relevant. Multiple studies document an increased incidence of cardiac events in TD MDS patients (Takatoku et al., 2007; Goldberg et al., 2010; Malcovati et al., 2005). Cardiac events were evaluated in TD patients undergoing IOL reduction with iron chelation therapy (ICT) (Remacha et al., 2015; Wong and Leitch, 2019). In 233 TD MDS patients, superior cardiac disease-free survival (DFS; congestive heart failure (CHF), arrythmias) was seen in patients receiving ICT (p = 0.02); multivariate analysis (MVA), p = 0.04 (Remacha et al., 2015; Sorror et al., 2007). Episodes of coronary artery disease, CHF, or arrythmias were delayed in TD patients receiving ICT (p = 0.02; (Wong and Leitch, 2019)). Hepatic dysfunction also occurs in TD MDS (Takatoku et al., 2007; Malcovati et al., 2005), and increased liver iron concentration (LIC) and elevated transaminases both decrease over a period of ICT (Gattermann et al., 2012a).

OS in multiple analyses is inferior in TD MDS (Malcovati et al., 2006; Sanz et al., 2008; de Swart et al., 2020; Hiwase et al., 2017). Non-controlled analyses suggest an OS benefit to receiving ICT (Remacha et al., 2015; Leitch et al., 2008; Rose et al., 2010; Neukirchen et al., 2012; Komrokji et al., 2011; Delforge et al., 2014; Zeidan et al., 2015; Langemeijer et al., 2016; Mainous et al., 2014; Hoeks et al., 2020; Liu et al., 2020; Zeidan et al., 2019). In the national Canadian MDS registry, though measures of frailty, comorbidity and disability at time of TD did not differ between non-ICT and ICT groups, median OS was significantly superior for ICT patients (p < 0.0001), MVA, p = 0.03 (Leitch et al., 2017). In the randomized, placebo-controlled study of ICT in MDS, despite half of placebo patients subsequently receiving ICT, there was superior event-free survival (EFS) with ICT (p = 0.015) (Angelucci et al., 2020).

An impact of IOL and IOL reduction on LFS are inconsistent. TD patients (n = 467) had inferior LFS (p < 0.0001) (Malcovati et al., 2006). In a Medicare study, TD MDS had a higher rate of AML progression (p < 0.001) (Goldberg et al., 2010). In one analysis, a delay in AML progression was seen in patients receiving ICT (p < 0.0001) (Lyons et al., 2013). However, in a matched pair analysis, there was no difference between groups in AML progression (Neukirchen et al., 2012). Similarly, in the Canadian registry analysis, LFS in the matched pairs did not differ significantly between groups (Leitch et al., 2017).

Infections are increased in TD MDS (Goldberg et al., 2010; Malcovati et al., 2005). Growth and replication of microorganisms is enhanced in an iron-rich environment, and IOL leads to functional impairment of neutrophils, macrophages & natural killer cells (Cantinieaux et al., 1987, 1990; Barton Pai et al., 2006; van Asbeck et al., 1984a, b; Nairz et al., 2014, 2015). In 138 RBC TD lower IPSS risk MDS, median time to first infection in patients receiving ICT was longer (p < 0.0001) (Wong et al., 2018).

Pre-clinical data suggest a suppressive effect of IOL on hematopoiesis (Hartmann et al., 2013; Chan et al., 2008; Okabe et al., 2014; Chai et al., 2015; Raaijmakers, 2014). In clinical studies of ICT in MDS, hematologic improvement (HI) is observed in a significant minority of patients (Angelucci et al., 2014; Gattermann et al., 2012b; Nolte et al., 2013; Jensen et al., 1996; Cilloni et al., 2011; List et al., 2012; Breccia et al., 2012; Maurillo et al., 2015; Rose et al., 2018; Messa et al., 2017). This effect may be relevant to clinical outcomes in MDS (reviewed in (Leitch and Gattermann, 2019).

Once transferrin is 80–85 % saturated, non-transferrin bound iron (NTBI) is detected in the peripheral blood (Sahlstedt et al., 2001). A subset of NTBI is redox-active labile plasma iron (LPI). Labile cellular iron (LCI) is also seen in IOL, as are ROS. These can be detected by simple flow-cytometry based techniques which are not yet validated and standardized for clinical use (Esposito et al., 2003; de Swart et al., 2018).

ROS may have significant consequences at a cellular and subcellular level (Nathan, 2003; Nathan and Cunningham-Bussel, 2013; Nathan and Ding, 2010). ROS suppress hepcidin, increasing GI iron import and reticuloendothelial system (RES) iron export, exacerbating IOL (Choi et al., 2007). Cancer cells commonly overproduce ROS, which leads to programmed cell death, and increases genomic instability, leading to DNA damage (Rassool et al., 2007; Sallmyr et al., 2008).

ROS confer signal specificity at the level of the amino acid, usually cysteine, by covalent modification, in contrast to the ionic interactions of macromolecules and phosphorylation that occur with classically defined cell signaling mechanisms (Denu and Tanner, 1998). For detailed discussion of the atomic specificity of ROS, see Nathan (Nathan and Cunningham-Bussel, 2013). Reactive nitrogen species are formed from the reaction of nitric oxide (NO) with oxygen or superoxide. These are also likely involved in toxicity to cells and macromolecules, and possibly in cell signaling, though their impact is less well studied, and they are not further discussed here (Nathan, 2003). ROS induce disulfide bond mediated homo- or hetero-dimerization. For example, ataxia telangiectasia mutated gene (ATM) kinase is directly activated by ROS via homodimerization leading to phosphorylation of heat shock protein 27 and subsequent activation of glucose 6 phosphate dehydrogenase (G6PD). The resulting nicotinamide adenine dinucleotide phosphate (NADPH) increase contributes to maintenance of cellular redox homeostasis. ROS-mediated heterodimerization of forkhead/winged helix box gene, group O proteins (FOXO) transcription factors and p300/cAMP response element binding (CREB) binding protein (CBP) acetyltransferase lead to acetylation of FOXO proteins and transcriptional activation (Nathan and Cunningham-Bussel, 2013). Another level of regulation of ROS signal transduction involves the peroxiredoxins (PRX) and possibly their post-translational regulation. For example, platelet derived growth factor receptor (PDGFR) phosphorylation is regulated by PRX2 (Choi et al., 2005).

Other exogenous sources of ROS include gamma irradiation, ultraviolet light, pollutants, and auto-oxidizing autacoids and xenobiotics, for example insecticides such as dichlorodiphenyltrichloroethane (DDT) (Nathan and Ding, 2010). Endogenous ROS sources include oxidases (NADPH oxidases or NOXs, xanthine oxidase), the mitochondrial electron transport chain (ETC), nitric oxide synthase (NOS), myeloperoxidase (MPO), eosinophil peroxidase, and endoplasmic reticulum (ER) oxidoreductin 1 (ero1) (Nathan and Ding, 2010).

Section snippets

Methods

Here the literature on oxidative stress, IOL and its relevance to subcellular and cellular physiology, and clinical relevance in MDS is reviewed. Pubmed searches were done, and searches of meeting abstracts from the American Society of Hematology, the European Hematology Association, the International Society for MDS, and the International BioIron meeting, back to 2010. Figures illustrating the cellular impact of oxidative stress on cardiomyocytes, hepatocytes, and hematopoietic stem cells, and

Organ toxicity; cardiac & hepatic

Hypothesis: IOL induced oxidative stress contributes to cardiac and hepatic morbidity, and infections.

Conclusions and future directions

Given the damaging effects of IOL-induced ROS in MDS, the medical potential of reducing oxidative stress depends on appropriate methods to identify and measure cellular and subcellular ROS. Challenges in developing sensitive and species-specific measurement tools and assays are considerable, but newer approaches outlined here appear promising. Three methods that may be used to detect oxidative stress are to measure ROS levels directly, measure oxidative damage to macromolecules, and to detect

Declaration of Competing Interest

Conflict of Interest statement: CK, no conflicts; HL, honoraria, research funding: AbbVie, Alexion, BMS, Celgene, Janssen, Novartis, Takeda, member of the Exjade Speaker’s Bureau.

Acknowledgements

CK was supported by a Summer Studentship from the Centre for Blood Research (CBR), University of British Columbia (UBC).

This article was conceived following a meeting on iron induced oxidative stress in MDS held as a satellite session to the Canadian Conference on MDS held in Banff, Canada in September 2014. Speakers at that session were: Rena Buckstein, University of Toronto; Norbert Gattermann, Heinrich-Heine University, Dusseldorff; John Porter, University College London; Vinod Pullarkat,

Cecilia Haymin Kim is an undergraduate student at Princeton University, pursuing a major in Chemistry and certificates in Global Health Policy and Materials Science. Her studies focus on the biological and medicinal applications of chemistry. Cecilia is particularly interested in the molecular mechanisms and effects of oxidative stress, as well as transfusional iron overload and chelation. She is a reviewer for various undergraduate-run research journals and a summer student member of the

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    Cecilia Haymin Kim is an undergraduate student at Princeton University, pursuing a major in Chemistry and certificates in Global Health Policy and Materials Science. Her studies focus on the biological and medicinal applications of chemistry. Cecilia is particularly interested in the molecular mechanisms and effects of oxidative stress, as well as transfusional iron overload and chelation. She is a reviewer for various undergraduate-run research journals and a summer student member of the Centre for Blood Research at the University of British Columbia.

    Dr. Heather Leitch is a Hematologist at St. Paul’s Hospital in Vancouver, Canada and Clinical Professor in the Department of Medicine at the University of British Columbia. Dr. Leitch has a clinical and research interest in transfusional iron overload in acquired anemias such as the myelodysplastic syndromes (MDS), and a longstanding interest in lymphoproliferative and other blood disorders in the setting of HIV infection. She is Director of Hematology/Oncology Research at St. Paul’s Hospital, a reviewer of scientific papers for multiple medical journals, and an active member of the UBC Department of Medicine Research Advisory Committee, the Canadian Consortium on MDS (CCMDS), the Canadian Hematology Society (CHS) and the American Society of Hematology (ASH).

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