这是用户在 2024-5-26 12:43 为 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933218/ 保存的双语快照页面,由 沉浸式翻译 提供双语支持。了解如何保存?
Skip to main content
U.S. flag

An official website of the United States government

Access keys 访问键 NCBI Homepage NCBI 主页 MyNCBI Homepage 我的 NCBI 主页 Main Content 主要内容 Main Navigation 主导航
2020; 11: 627662.
Front Immunol. 2020; 11: 627662.
Published online 2021 Feb 19. doi: 10.3389/fimmu.2020.627662
2021 年 2 月 19 日在线发表。doi:10.3389/fimmu.2020.627662
PMCID: PMC7933218 PMCID:PMC7933218
PMID: 33679722 PMID:33679722

The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia

Sarah Weber, 1 , 2 , * , Anastasia Parmon, 1 , Nina Kurrle, 1 , 2 , 3 Frank Schnütgen, 1 , 2 , 3 and Hubert Serve 1 , 2 , 3 , *
Sarah Weber, 1 , 2 , * , Anastasia Parmon, 1 , Nina Kurrle, 1 , 2 , 3 Frank Schnütgen, 1 , 2 , 3 和 Hubert Serve 1 , 2 , 3 , *

Abstract 摘要

Myelodysplasticsyndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs. Here, we provide an overview of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML.
骨髓增生异常综合征(MDS)和急性髓系白血病(AML)是导致功能性血细胞形成不足的克隆性造血干细胞疾病。疾病固有因素如红细胞生成不足和治疗相关因素如反复输注红细胞的治疗经常导致 MDS 和 AML 患者体内铁超载。此外,与铁代谢相关的蛋白质的功能和表达的改变越来越被认为是这些疾病的发病因素和潜在易感性因素。铁已知参与多种细胞内外过程。它对细胞代谢以及细胞增殖至关重要,并与活性氧自由基的形成密切相关。因此,铁可以影响克隆性髓样疾病的进程、白血病环境以及感染的发生和防御。铁稳态失衡可能导致正常细胞和恶性细胞的死亡。 利用铁稳态的重要性的新潜在治疗策略包括铁螯合、调节参与铁代谢的蛋白质、通过铁死亡诱导白血病细胞死亡以及利用铁蛋白传递抗白血病药物。在这里,我们提供了关于铁在 MDS 和 AML 患者中功能、预后影响和潜在治疗策略的一些最新发现的概述。

Keywords: myelodysplastic syndrome, acute myeloid leukemia, iron overload, reactive oxygen species, microenvironment, iron chelation

Introduction 介绍

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) represent heterogeneous clonal hematopoietic stem cells disorders. MDS is characterized by dysplasia of hematopoietic cells, AML by uncontrolled proliferation of poorly differentiated hematopoietic cells (blasts). Both diseases lead to insufficient hematopoiesis. Chronic fatigue due to anemia, bleeding due to thrombocytopenia and infection due to neutropenia are typical consequences. MDS bone marrow is prone to leukemic transformation with approximately 30% of MDS patients developing secondary AML over time (). AML, being the most common acute leukemia in adults, is a disease that in most cases needs immediate treatment to avoid death within months or even weeks. Although our knowledge about the molecular drivers of AML is rapidly increasing, and recently resulted in the development of novel drugs and of molecularly informed treatment stratification, the 5-year overall survival (OS) rate is still below 30% ().
骨髓增生异常综合征(MDS)和急性髓系白血病(AML)代表异质性克隆性造血干细胞疾病。MDS 的特征是造血细胞的畸形,AML 则是由未分化造血细胞(幼稚细胞)的不受控增殖所表现。这两种疾病都会导致造血不足。慢性疲劳是由贫血引起的,出血是由血小板减少引起的,感染是由中性粒细胞减少引起的,这些都是典型后果。MDS 骨髓容易发生白血病转化,大约 30%的 MDS 患者随着时间发展会发展为继发性 AML。AML 是成人中最常见的急性白血病,大多数情况下需要立即治疗,以避免在几个月甚至几周内死亡。尽管我们对 AML 的分子驱动因素的了解正在迅速增加,并最近导致了新药物的开发和分子信息治疗分层,但 5 年总生存率仍然低于 30%。

MDS and AML patients may develop primary iron overload arising from insufficient erythropoiesis (). Repeated transfusions, which aim at ameliorating the symptoms of anemia, often lead to secondary iron overload. Iron overload in MDS and AML patients may lead to multiple cellular and systemic changes and therefore plays a crucial role in these hematologic malignancies ( Figure 1 ). Besides the importance of iron and proteins involved in iron metabolism for multiple cellular functions, iron is tightly connected to the production of reactive oxygen species (ROS) and can lead to cell death when in excess (). Iron overload in the bone marrow and other tissues can result in alterations of the microenvironment and contribute to increased morbidity (). In this respect, iron has been demonstrated to participate in aggravating the symptoms of MDS and AML patients by contributing to bone marrow failure (). Excess iron can also alter the components of the immune system and result in an increased susceptibility to various infections (). Therefore, serum and cellular iron levels have a prognostic value at initial diagnosis, might influence the response to chemotherapy and predict the outcome after hematopoietic stem cell transplantation (HSCT) (). The involvement of iron in diverse metabolic processes and its special necessity for malignant cells makes it an interesting therapeutic target ().
MDS 和 AML 患者可能由于红细胞生成不足而发展出原发性铁过载(3)。旨在改善贫血症状的反复输血往往导致继发性铁过载。MDS 和 AML 患者的铁过载可能导致多种细胞和系统变化,因此在这些血液恶性肿瘤中起着至关重要的作用(图 1)。除了铁及参与铁代谢的蛋白对多种细胞功能的重要性外,铁与活性氧自由基(ROS)的产生密切相关,当过量时可导致细胞死亡(4)。骨髓和其他组织中的铁过载可能导致微环境的改变,并导致发病率增加(5)。在这方面,铁已被证明通过促进骨髓衰竭而加重 MDS 和 AML 患者的症状。过量的铁还可以改变免疫系统的组成,并导致对各种感染的易感性增加(7)。 因此,血清和细胞铁水平在初步诊断时具有预后价值,可能影响化疗的反应,并且可以预测造血干细胞移植(HSCT)后的结果。铁在多种代谢过程中的参与以及对恶性细胞的特殊必要性使其成为一个有趣的治疗靶点。

An external file that holds a picture, illustration, etc.
Object name is fimmu-11-627662-g001.jpg

Potential cellular and systemic consequences of iron overload in patients with MDS or AML. Many of these factors are interwoven and may all together contribute to patient outcome.
MDS 或 AML 患者铁过载的潜在细胞和系统后果。许多这些因素相互交织,可能共同影响患者的预后。

In this review, we will first give an overview of the molecular basis of iron metabolism and its role in hematopoiesis. We will then focus on the altered iron metabolism in MDS and AML patients including clinical consequences. Subsequently, we will elucidate the effect of iron overload on the pathophysiology of MDS and AML, clinical consequences of the altered iron metabolism and its use as a potential target for therapy.
在这篇评论中,我们将首先概述铁代谢的分子基础及其在造血过程中的作用。然后,我们将重点关注 MDS 和 AML 患者中铁代谢的改变,包括临床后果。随后,我们将阐明铁过载对 MDS 和 AML 病理生理学的影响,改变后的铁代谢的临床后果以及其作为潜在治疗靶点的用途。

Iron Homeostasis and its Role for Normal Hematopoiesis

Iron is an essential micronutrient for fundamental metabolic processes in all cells and organisms and is therefore a crucial element for terrestrial life. A vital iron-binding protein of the human body is hemoglobin, which is crucial for the transport, storage and distribution of oxygen. Hemoglobin in circulating erythrocytes and erythroid precursors in the bone marrow contains about two thirds of the total body iron (). Besides, iron is bound to myoglobin in the muscles. Iron is also part of prosthetic groups such as in cytochrome proteins and Fe-S clusters due to its ability to facilitate electron transfer. Thereby, it is essential for the function of the citric acid cycle (TCA), the respiratory chain, DNA synthesis and DNA repair.
铁是所有细胞和生物体中基本代谢过程的必需微量营养素,因此对陆地生命至关重要。人体中一种重要的铁结合蛋白是血红蛋白,对氧气的运输、储存和分配至关重要。循环红细胞和骨髓中的红细胞前体中的血红蛋白含有大约全身铁的三分之二。此外,铁结合在肌肉中的肌红蛋白中。铁还是辅基团的一部分,如细胞色素蛋白和 Fe-S 簇,由于其促进电子转移的能力。因此,它对柠檬酸循环(TCA)、呼吸链、DNA 合成和 DNA 修复的功能至关重要。

Systemic iron homeostasis is maintained by a balance of iron uptake, recycling and loss ( Figure 2A ). Nutritional iron is mainly available as ferric iron, which can be reduced by ferrireductases. Subsequently, ferrous iron can be internalized into enterocytes via need-oriented gastrointestinal active transport mechanisms by the divalent metal ion transporter (SLC11A2). Iron may also be internalized through siderophore-associated binding to lipocalin-2 (LCN2) and subsequent endocytosis (). Moreover, nutritional heme and possibly also ferritin can be absorbed by enterocytes via mechanisms not fully determined yet (). Efflux of iron across the basolateral membrane into the bloodstream via ferroportin (SLC40A1), the only known iron exporter, is usually followed by its oxidation to ferric iron by the membrane-bound ferroxidase hephaestin. Ferric iron can be loaded to transferrin (TF) and then be used for the needs of the body. Excess iron is stored via ferritin (FTH and FTL) mainly in the liver. The body loses iron via exfoliation of cells on the inner and outer surfaces of the body with stool, urine, sweat and blood loss in menstruating women, but there are no physiological active excretion mechanisms to release an excess of iron in mammals and humans and the iron excretion cannot physiologically be increased beyond these values. High iron levels lead to systemic secretion of hepcidin, the most relevant regulator of the systemic iron metabolism, by the liver. Hepcidin binds to ferroportin on enterocytes and iron-storing cells like macrophages, resulting in an internalization and degradation of the hepcidin-ferroportin complex and thus effectively shuts down nutritional iron absorption and iron release from internal iron storage. Hepcidin expression is controlled by regulatory feedback mechanisms that involve active erythropoiesis: erythroblast-derived erythroferrone (ERFE), growth differentiation factor 11 (GDF11), growth differentiation factor 15 (GDF15) and twisted gastrulation protein homolog 1 (TWSG1) have been shown to influence hepatic hepcidin secretion, thus linking erythropoietic iron demand to iron supply ().
系统铁稳态是通过铁的摄取、回收和丢失的平衡来维持的(图 2A)。营养铁主要以三价铁的形式存在,可以被铁还原酶还原。随后,二价铁可以通过双价金属离子转运蛋白(SLC11A2)的需要性胃肠活跃转运机制内化到肠细胞中。铁也可以通过铁载体相关结合到脂联素-2(LCN2)并随后内吞而内化(13)。此外,营养血红素和可能也是铁蛋白可以通过尚未完全确定的机制被肠细胞吸收(14)。铁通过铁转运蛋白(SLC40A1)跨基底侧膜进入血液,这是已知的唯一铁输出蛋白,通常随后通过膜结合的铁氧化酶赫费斯汀氧化为三价铁。三价铁可以装载到转铁蛋白(TF)中,然后用于身体的需求。多余的铁主要储存在肝脏中的铁蛋白(FTH 和 FTL)中。 身体通过排便、尿液、汗液和女性月经期间的血液流失,通过身体内外表面细胞的脱落而丢失铁元素,但在哺乳动物和人类中没有生理活跃的排铁机制来释放过量的铁元素,铁元素的排泄在生理上不能超出这些值。高铁水平导致肝脏系统性分泌肝铁素调节蛋白(hepcidin),这是系统性铁代谢最相关的调节因子。肝铁素调节蛋白结合到肠细胞和铁储存细胞(如巨噬细胞)上的铁转运蛋白,导致肝铁素调节蛋白-铁转运蛋白复合物的内化和降解,从而有效地关闭营养铁的吸收和内部铁储存的释放。肝铁素调节蛋白的表达受到调节性反馈机制的控制,这些机制涉及活跃的红细胞生成:已经显示红细胞前体细胞衍生的红细胞铁素(ERFE)、生长分化因子 11(GDF11)、生长分化因子 15(GDF15)和扭曲胃肠蛋白同源物 1(TWSG1)影响肝脏肝铁素调节蛋白的分泌,从而将造血铁需求与铁供应联系起来。

An external file that holds a picture, illustration, etc.
Object name is fimmu-11-627662-g002.jpg

Iron metabolism under physiological conditions (A) and in case of MDS/AML (B). Black arrows indicate direct iron metabolism, gray arrows represent regulatory mechanisms. LPI, labile plasma iron; MPS, mononuclear phagocyte system; NTBI, non-transferrin-bound iron; TFBI, transferrin-bound iron.
在生理条件(A)和 MDS/AML 情况下(B)的铁代谢。黑箭头表示直接铁代谢,灰箭头代表调节机制。LPI,易变性血浆铁;MPS,单核吞噬细胞系统;NTBI,非转铁蛋白结合铁;TFBI,转铁蛋白结合铁。

Overall, only 4% to 10% of the daily iron need is supplied by uptake of nutritional iron, whereas the majority of iron gets recycled by different cell types originating from the bone marrow. Cells within the mononuclear phagocyte system (MPS) remove senescent blood cells via phagocytosis and digestion. Afterwards, iron is released into the blood, from where it is transported by transferrin back to the bone marrow for recurrent use in hematopoiesis. About ten times the amount of serum transferrin iron is recycled through this bone marrow-MPS-bone marrow cycle per day ().
总体而言,每天摄入的营养铁只能满足日常需求的 4%至 10%,而大部分铁都是由源自骨髓的不同细胞类型循环利用的。单核吞噬细胞系统(MPS)内的细胞通过吞噬和消化去除老化的血细胞。随后,铁释放到血液中,通过转铁蛋白被输送回骨髓,用于再生造血。每天通过这种骨髓-MPS-骨髓循环回收的血清转铁蛋白铁量是血清转铁蛋白铁量的十倍(19)。

Intracellular iron acquisition is provided by ferrous iron importers (SLC11A2, SLC39A8, SLC39A14) or by binding of diferric transferrin to the cell surface transferrin receptors (TFR: TFRC and TFR2α) resulting in an internalization of the complex by clathrin-mediated endocytosis. Acidification of the endosome results in the release of ferric iron from transferrin. Additionally, circulating FTH can bind transferrin-independently to TFRC and be internalized in this way (). Endosomal ferric iron is reduced to ferrous iron via ferrireductases. Ferrous iron can then be transported to the cytosol, where it represents the labile cellular iron (LCI) pool. This non-bound, redox-active and chelatable iron pool can be utilized in cellular metabolic processes, or, when in excess, be stored in ferritin or excreted via ferroportin. NCOA4 can mediate ferritinophagy, while it is degraded via HERC2 ubiquitination-mediated induction of the proteasomal degradation machinery in the presence of iron (). Intracellular iron proteins are post-transcriptionally regulated by the IRP/IREs regulatory network. Therefore, mRNAs of regulated proteins harbor specific hairpin stem loops, called iron-responsive elements (IRE), situated in the 3’ or 5’ untranslated regions. In iron-deplete cells, the iron-responsive element binding proteins ACO1 and IREB2 bind to the IREs of specific mRNAs resulting in mRNA stabilization or translational repression of these mRNAs. In this way, they modulate the expression of iron-regulating proteins, which subsequently leads to an increase of the labile iron pool. In iron-replete cells, ACO1 works instead as aconitase in the TCA cycle and IREB2 undergoes SCFFBXL5 E3 ubiquitin ligase mediated ubiquitination and proteasomal degradation ().
细胞内铁的获取由亚铁铁导入蛋白(SLC11A2、SLC39A8、SLC39A14)提供,或者通过双铁转铁蛋白与细胞表面转铁蛋白受体(TFR: TFRC 和 TFR2α)的结合,导致复合物通过衬氨酸介导的内吞作用而内化。内体的酸化导致铁蛋白中的三价铁释放。此外,循环的 FTH 可以独立于转铁蛋白地结合到 TFRC 并以这种方式内化(20)。内体中的三价铁通过铁还原酶还原为亚铁,亚铁随后可以被运送到细胞质,其中它代表了易变的细胞铁(LCI)库。这种非结合的、氧化还原活性和可螯合的铁库可以在细胞代谢过程中被利用,或者在过量时被储存在铁蛋白中或通过铁转运蛋白排泄。NCOA4 可以介导铁蛋白吞噬,同时在铁存在的情况下通过 HERC2 泛素化介导诱导蛋白酶体降解机制而被降解(21)。细胞内铁蛋白受 IRP/IREs 调控网络的后转录调控。 因此,受调控蛋白的 mRNA 携带特定的发夹状茎环,称为铁响应元件(IRE),位于 3'或 5'非翻译区。在缺铁细胞中,铁响应元件结合蛋白 ACO1 和 IREB2 结合到特定 mRNA 的 IRE,导致这些 mRNA 的稳定或翻译抑制。通过这种方式,它们调节铁调控蛋白的表达,从而导致可变铁库的增加。在富铁细胞中,ACO1 反而作为 TCA 循环中的顺式异柠檬酸脱水酶,IREB2 经历 SCF E3 泛素连接酶介导的泛素化和蛋白酶体降解。

Both, iron deficiency and iron overload lead to impaired hematopoietic functions. Iron deficiency resulting in microcytic anemia due to impaired hemoglobin production is a common nutritional deficiency disorder affecting especially women and children worldwide. As a consequence of iron overload, dysplastic changes and detrimental effects on erythroblast differentiation and maturation resulting in a reduction of the proliferative capacity of erythropoiesis and of erythroblast apoptosis in vitro have been described (, ). Additionally, iron overload has been shown to induce growth arrest and cell death due to oxidative stress via ROS-mediated activation of p38MAPK, JNK and p53 pathways in immature hematopoietic cells (, ). Thereby, the IRP/IRE regulatory network is essential in maintaining hematopoietic stem cells in their physiological self-renewal process. While Ireb2(-/-) mice develop microcytic anemia, deletion of Fbxl5 in murine hematopoietic stem cells leads to impaired hematopoiesis due to Ireb2 overexpression and subsequent iron overload (, ).
缺铁和铁过载都会导致造血功能受损。由于受损的血红蛋白产生而导致的微小细胞性贫血是一种常见的营养缺乏症,特别影响全球妇女和儿童。铁过载的结果是造血功能异常,对红细胞前体细胞的分化和成熟产生不良影响,导致红细胞生成能力和体外红细胞前体细胞凋亡的降低(3, 23)。此外,铁过载已被证明通过 ROS 介导的 p38MAPK、JNK 和 p53 途径诱导生长停滞和细胞死亡,由于氧化应激在未成熟造血细胞中的激活(24, 25)。因此,IRP/IRE 调控网络对于维持造血干细胞的生理自我更新过程至关重要。虽然 Ireb2(-/-)小鼠会发展微小细胞性贫血,但在小鼠造血干细胞中删除 Fbxl5 会导致由于 Ireb2 过度表达和随后的铁过载而导致造血功能受损(26, 27)。

Elevated Iron Levels in MDS and AML Patients
MDS 和 AML 患者的铁水平升高

Measurement of a patient’s iron status is difficult due to various pitfalls of the available methods. Most commonly, iron status is measured based on serum iron indicators such as serum ferritin, transferrin saturation and soluble transferrin receptor (sTFR). However, the results may be influenced by external factors including inflammation, growth factors and organ dysfunctions (). In case of acute iron overload, exceedance of the transferrin binding capacity leads to detectable amounts of non-transferrin-bound iron (NTBI) in the serum. A subfraction of NTBI is chemically labile plasma iron (LPI), which is toxic due to its redox-activity and can cause oxidative damage to cellular membranes, proteins and DNA (). NTBI including LPI are loosely bound to serum components as albumin and citrate (). Thereby, the presence and dynamics of active iron forms as NTBI and LPI may be accountable for direct toxic effects, whereas steady iron markers as ferritin may reflect mainly systemic changes in iron metabolism. Iron overload can also be measured via organ biopsies or imaging methods as biomagnetic susceptometry or magnetic resonance imaging (MRI) although these methods are rarely applied due to their invasiveness, costs or insufficient validation ().
患者铁状态的测量由于现有方法的各种缺陷而变得困难。最常见的是,铁状态是基于血清铁指标(如血清铁蛋白、转铁蛋白饱和度和可溶性转铁蛋白受体(sTFR))来衡量的。然而,结果可能会受到包括炎症、生长因子和器官功能障碍在内的外部因素的影响。在急性铁超载的情况下,超过转铁蛋白结合能力会导致血清中可检测到非转铁蛋白结合铁(NTBI)的量。NTBI 的一个亚分数是化学不稳定的血浆铁(LPI),由于其氧化还原活性,可能对细胞膜、蛋白质和 DNA 造成氧化损伤。NTBI 包括 LPI 松散地结合在血清成分如白蛋白和柠檬酸中。因此,活性铁形式如 NTBI 和 LPI 的存在和动态可能对直接毒性效应负责,而稳定的铁标记物如铁蛋白可能主要反映铁代谢中的系统变化。 铁过载也可以通过器官活检或成像方法来测量,如生物磁感应法或磁共振成像(MRI),尽管这些方法很少被应用,因为它们具有侵入性、成本高或验证不足(31)。

Using this variety of methods, over the years several characteristics of an altered iron metabolism in MDS and AML patients have been found together indicating a state of iron overload in these diseases ( Figure 2B ).
利用这种各种方法,多年来已经发现了 MDS 和 AML 患者铁代谢异常的几个特征,表明这些疾病存在铁过载的状态(图 2B)。

The most common reason for iron overload in patients with hematologic diseases is the administration of multiple red blood cell transfusions representing a massive excess of iron uptake with about 200 mg of iron in one unit of packed red blood cells (). Transfusion-associated iron is processed by hepatic and splenic macrophages, which recycle heme iron from erythrocytes and release it into the extracellular space, thereby increasing the serum iron pool.
患有血液学疾病的患者出现铁过载的最常见原因是多次输注红细胞制剂,这代表了大量的铁摄入,每单位浓缩红细胞中含有约 200 毫克铁。输血相关的铁由肝脏和脾脏的巨噬细胞处理,这些细胞从红细胞中回收血红素铁并释放到细胞外空间,从而增加血清铁库。

Independent of red blood cell transfusions, disease-immanent factors can contribute to the iron overload phenotype. Dysplastic ineffective erythropoiesis is one of the cardinal manifestations of MDS, leading to an insufficient production of mature erythrocytes and potentially to a higher turnover of erythroid progenitors. This insufficient erythropoiesis leads to the secretion of hepcidin-suppressing cytokines and thus might result in further iron overload. A vicious cycle is formed, in which primary bone marrow dysfunction causes iron overload, which in turn amplifies bone marrow dysfunction. The presence of this mechanism is supported by data from Cui et al., who found elevated hepcidin and ferritin levels, but a reduced hepcidin/ferritin ratio compared to healthy controls in a study including 107 MDS patients without prior transfusions (). In the same study, elevated ferritin levels correlated with decreased proliferative potential of erythropoiesis ex vivo. However, the extent of these mechanisms seems to differ between MDS subtypes. MDS subtypes with a high presence of ring sideroblasts (RARS, corresponding to MDS-RS according to the present WHO classification) as a morphological correlate of iron-loaded mitochondria, have been shown to have the lowest hepcidin/ferritin ratio (, ). Therefore, inefficient erythropoiesis might be more prominent in these subtypes than in other MDS patients. Correspondingly, MDS-RS is typically associated with a mutation in the splicing factor gene SF3B1. An SF3B1 mutation was recently identified by Bondu et al. to lead to the expression of an alternative ERFE transcript, which suppresses hepcidin transcription and thereby provides an explanation for the increased iron load especially in these patients (). The European MDS registry (EUMDS) investigated the occurrence of iron overload in MDS patients prospectively (). Here, clinical data and iron metabolism-associated parameters including serum levels of ferritin, transferrin, hepcidin, GDF15, sTFR, NTBI and LPI were analyzed in newly diagnosed lower-risk MDS patients from 148 centers in 16 countries in Europe and Israel since 2008. The results indicate that the above-mentioned concept of primary, disease-immanent iron overload may not be of strong relevance for the majority of MDS patients: markers of iron overload were elevated over all MDS subtypes. However, occurrence specifically correlated with transfusion-dependent MDS and with the MDS-RS subtype.
独立于红细胞输血,疾病固有因素可能导致铁过载表型。畸形无效的造血是 MDS 的主要表现之一,导致成熟红细胞的生产不足,可能导致红细胞祖细胞的更高周转率。这种不足的造血导致肝素抑制细胞因子的分泌,从而可能导致进一步的铁过载。形成了一种恶性循环,即原发性骨髓功能障碍导致铁过载,进而增强骨髓功能障碍。此机制的存在得到了 Cui 等人的数据支持,他们在一项研究中发现,与未接受输血的 107 名 MDS 患者相比,肝素和铁蛋白水平升高,但肝素/铁蛋白比值降低(33)。在同一研究中,升高的铁蛋白水平与体外红细胞增殖潜力降低相关。然而,这些机制的程度似乎在 MDS 亚型之间有所不同。 MDS 亚型中具有高比例环状铁染色体(RARS,根据目前的 WHO 分类对应于 MDS-RS)作为铁负荷线粒体的形态学相关物,已被证明具有最低的肝铁蛋白/铁蛋白比值(34, 35)。因此,这些亚型中的效率低下的造血可能比其他 MDS 患者更为突出。相应地,MDS-RS 通常与剪接因子基因 SF3B1 的突变相关联。最近 Bondu 等人发现 SF3B1 突变导致表达一种替代 ERFE 转录本,抑制肝铁蛋白转录,从而解释了特别是这些患者中铁负荷增加的原因(36)。欧洲 MDS 登记处(EUMDS)前瞻性调查了 MDS 患者中铁过载的发生(37)。自 2008 年以来,148 个中心在欧洲和以色列的 16 个国家中对新诊断的低风险 MDS 患者进行了临床数据和与铁代谢相关的参数的分析,包括铁蛋白、转铁蛋白、肝铁蛋白、GDF15、sTFR、NTBI 和 LPI 的血清水平。 结果表明,上述关于原发性、疾病内在性铁过载概念可能对大多数 MDS 患者并不具有强相关性:铁过载标志物在所有 MDS 亚型中均升高。然而,发生特别与依赖输血的 MDS 和 MDS-RS 亚型相关。

During chemotherapy and foremost during hematopoietic stem cell transplantation (HSCT) the iron homeostasis might be further disturbed as a result of erythroid cell lysis and suppressed erythropoiesis. This theory matches data from the German prospective multicenter study ALLIVE including 22 MDS and 90 AML patients and some smaller studies, which show an increase in NTBI and LIP levels during allogeneic HSCT ().
在化疗期间,尤其是在造血干细胞移植(HSCT)期间,由于红细胞溶解和红细胞生成受抑制,铁稳态可能会进一步受到干扰。这一理论与德国前瞻性多中心研究 ALLIVE 的数据相吻合,该研究包括 22 例 MDS 和 90 例 AML 患者以及一些较小的研究,这些研究显示在同种异体 HSCT 期间 NTBI 和 LIP 水平增加(38-40)。

During the course of AML, signs of iron overload have also been described. Frequently, serum ferritin is elevated at initial AML diagnosis. The extent correlates with the leukemic burden, normalizes in remission, and increasing levels may signify a relapse (). Increased hepcidin serum levels at diagnosis and pre- as well as post-HSCT were described in two small cohorts including exclusively or mostly AML patients (, ). However, hepcidin and ferritin are acute-phase proteins and might not only indicate iron overload but may also reflect a state of inflammation. Correspondingly, ferritin and hepcidin serum levels in one of these studies correlated with serum levels of CRP and IL-6 (). In another study, ferritin levels were also elevated in CRP-low patients and ferritin and hepcidin levels correlated with the number of blood transfusions (). Overall, valid data including definitive measures of iron overload and investigations in the systemic iron state in AML are missing. Specifically, there are no data available from investigating the interplay of insufficient hematopoiesis and iron metabolism in AML. Presumably, ineffective erythropoiesis due to dysplastic changes applies only to an AML subgroup (especially AML with myelodysplasia-related changes), whereas in other AML subtypes, insufficient erythropoiesis may rather be driven by other pathomechanisms as the suppression of erythropoiesis by inflammatory cytokines ().
在 AML 的过程中,也描述了铁过载的迹象。通常,在初步 AML 诊断时,血清铁蛋白水平升高。其程度与白血病负担相关,缓解时会恢复正常,而升高的水平可能表明复发(41)。两个小队列中描述了诊断时和 HSCT 前后铁调蛋白血清水平升高,这两个队列仅或主要包括 AML 患者(42, 43)。然而,铁调蛋白和铁蛋白是急性期蛋白,可能不仅指示铁过载,还可能反映炎症状态。相应地,其中一项研究中,铁蛋白和铁调蛋白血清水平与 CRP 和 IL-6 的血清水平相关(42)。在另一项研究中,CRP 低的患者铁蛋白水平也升高,铁蛋白和铁调蛋白水平与输血次数相关(43)。总的来说,缺乏包括铁过载的明确措施和 AML 系统铁状态调查在内的有效数据。具体来说,目前没有可用于调查 AML 中造血不足和铁代谢相互作用的数据。 据推测,由于发育异常变化导致的无效红细胞生成仅适用于 AML 亚组(特别是具有骨髓增生异常相关变化的 AML),而在其他 AML 亚型中,红细胞生成不足可能更多地受到其他病理机制的驱动,如炎症细胞因子对红细胞生成的抑制。

Signs of iron overload show a prognostic impact in both, MDS and AML patients in many studies. One of the open questions in the field is, whether iron overload is just a consequence of increased transfusion frequency, which is a well-known measure of disease severity, which would explain the worse prognosis, or, whether iron overload per se has a negative impact on the course of the disease. In both diseases, the degree of transfusion dependency was associated with a worse patient outcome (). However, high levels of LPI were associated with inferior overall and progression-free survival in lower-risk MDS patients irrespective of the transfusion status in the study of the European MDS registry (). The ALLIVE study revealed that in patients undergoing allogeneic HSCT, pretransplant NTBI was associated with an increased incidence of non-relapse mortality and a worse overall survival, which is hard to explain by the pretransplant disease severity alone (). Besides, high serum ferritin levels at AML diagnosis were associated with a worse outcome (, , ). The same is true for ferritin levels before and after allogeneic HSCT in cohorts including mainly MDS and AML patients (, ). Data on the prognostic impact of the liver iron content measured by MRI for patients receiving allogeneic HSCT are ambiguous. While a meta-analysis of four studies with mixed patient cohorts including overall 50% AML and 16% MDS patients found that increased liver iron was not indicative for bad patient outcome (), the ALLIVE study showed an association of high pretransplant liver iron with increased early non-relapse mortality (NRM) (). Despite different compositions of the patient cohorts with older, more severely iron-overloaded patients in the ALLIVE study, the role for liver iron overload in NRM remains inconclusive.
铁过载的迹象在许多研究中显示出对 MDS 和 AML 患者的预后影响。该领域中一个未解之谜是,铁过载是否仅是增加输血频率的结果,这是疾病严重程度的一个众所周知的衡量标准,这可以解释更糟糕的预后,或者铁过载本身是否对疾病进程产生负面影响。在这两种疾病中,输血依赖程度与患者预后更差相关(45-48)。然而,在欧洲 MDS 登记研究中,无论输血状况如何,高水平的 LPI 与低风险 MDS 患者的整体生存率和无进展生存率不利相关(37)。ALLIVE 研究表明,在接受同基因异体 HSCT 的患者中,移植前 NTBI 与非复发死亡率的增加和整体生存率的恶化相关,这很难仅通过移植前疾病严重程度来解释(38)。此外,在 AML 诊断时高血清铁蛋白水平与更糟糕的预后相关(9, 49, 50)。 同样适用于主要包括 MDS 和 AML 患者的队列在异基因 HSCT 之前和之后的铁蛋白水平(51,52)。关于通过 MRI 测量的肝铁含量对接受异基因 HSCT 患者的预后影响的数据是模棱两可的。虽然一项涵盖总体 50% AML 和 16% MDS 患者的混合患者队列的四项研究的荟萃分析发现增加的肝铁并不预示患者预后不良(53),但 ALLIVE 研究显示了移植前高肝铁与早期非复发死亡率(NRM)增加的关联(38)。尽管 ALLIVE 研究中患者队列的组成不同,包括年龄较大、铁过载严重的患者,但肝铁过载在 NRM 中的作用仍然没有定论。

Taking the data on the prognostic impact of different iron overload markers together, the overall correlation with patient outcome is striking. However, it is difficult to exclude that this is merely the reflection of disease severity. Despite these doubts, clinical correlation data and studies on the consequences of iron overload from other diseases, led to the widespread recommendation to treat transfusion-induced iron overload in patients with hematological malignancies. Several therapeutic options are available that will be reviewed in section Therapies Aiming at Iron Metabolism as a Possible Target in MDS and AML.
将不同铁过载标志物的预后影响数据综合在一起,与患者预后的整体相关性显著。然而,很难排除这仅仅是疾病严重程度的反映。尽管存在这些疑虑,临床相关数据和关于其他疾病引起的铁过载后果的研究,导致广泛推荐在患有血液恶性肿瘤的患者中治疗输血诱导的铁过载。有几种治疗选择可供选择,将在《治疗以铁代谢为可能靶点的 MDS 和 AML 部分》中进行审查。

Potential Roles of Iron-Related Intracellular Proteins in AML and MDS
AML 和 MDS 中与铁相关的细胞内蛋白质的潜在作用

To further understand the iron metabolism in MDS and AML, investigating the role of iron-related intracellular proteins might help explaining the interplay between iron and essential intracellular networks in MDS and AML cells.
为了进一步了解 MDS 和 AML 中的铁代谢,调查与铁相关的细胞内蛋白质的作用可能有助于解释 MDS 和 AML 细胞中铁与必要细胞内网络之间的相互作用。

Expression of iron-importing proteins might be an indicator for the iron need of the cells. It has been appreciated for almost 40 years that AML cells strongly bind to transferrin (). In humans, two transferrin-binding receptors have been identified: TFRC is a ubiquitously expressed high affinity receptor and TFR2α is restricted to certain cell types as hepatocytes and erythroblasts and has an approximately 25-fold lower affinity for transferrin than TFRC (, ). The alternative TFR2 isoform, TFR2β, lacks the transmembrane and cytoplasmic domain but might be involved in the regulation of iron efflux in the MPS (). Overexpression of TFRC was demonstrated in AML cells () and supports the hypothesis of a higher iron consumption of these cells. Thereby, TFRC expression was higher in undifferentiated than in more differentiated AML subtypes and decreased with terminal differentiation (, ). Neither high TFRC mRNA nor TFRC protein levels in AML cells correlated with patient outcome although a correlation was found with increased anemia, thrombopenia and complex cytogenetics (, ). On the contrary, higher TFR2 mRNA levels in bone marrow samples were surprisingly associated with a favorable outcome in AML and MDS patients (, ). However, the increase of TFR2 mRNA levels in MDS and AML bone marrow samples were shown to roughly correlate with the proportion of erythroid cells in the marrow and might therefore only to a minor extent reflect the expression of MDS or AML cells themselves (, ). This association with the erythroid cell number might be the explanation for the favorable outcome. Deducing from these data, higher TFRC expression of AML cells might reflect an undifferentiated blast status whereas higher TFR2 mRNA expression in the bone marrow of MDS and AML patients might be a marker for the number of erythroid cells. However, there is also evidence for a need of higher iron amounts due to overall higher TFRC expression and the necessity of TFR for leukemic cell growth as shown in TFR antibody studies described in section Perspectives.
铁进口蛋白的表达可能是细胞对铁需求的指标。近 40 年来,人们已经认识到 AML 细胞强烈结合转铁蛋白(54)。在人类中,已经鉴定出两种转铁蛋白结合受体:TFRC 是广泛表达的高亲和力受体,TFR2α仅限于某些细胞类型,如肝细胞和红细胞前体细胞,并且对转铁蛋白的亲和力约为 TFRC 的 25 倍(55, 56)。另一种 TFR2 亚型 TFR2β缺乏跨膜和胞质结构域,但可能参与 MPS 中铁外流的调节(57)。在 AML 细胞中已证明 TFRC 的过表达(58-60),并支持这些细胞对铁的更高消耗的假设。因此,TFRC 的表达在未分化 AML 亚型中高于更为成熟的亚型,并随着终末分化而降低(59, 61)。AML 细胞中的 TFRC mRNA 或 TFRC 蛋白水平高与患者预后无关,尽管发现与贫血、血小板减少和复杂的细胞遗传学有关(62, 63)。 相反,骨髓样本中较高的 TFR2 mRNA 水平与 AML 和 MDS 患者的良好预后惊人地相关(64, 65)。然而,MDS 和 AML 骨髓样本中 TFR2 mRNA 水平的增加似乎与骨髓中红细胞的比例大致相关,因此可能只在很小程度上反映 MDS 或 AML 细胞本身的表达(13, 66)。这种与红细胞数量的关联可能是有利结果的解释。根据这些数据推断,AML 细胞的较高 TFRC 表达可能反映未分化的爆发状态,而 MDS 和 AML 患者骨髓中较高的 TFR2 mRNA 表达可能是红细胞数量的标志。然而,也有证据表明,由于整体 TFRC 表达较高以及 TFR 对白血病细胞生长的必要性,需要更多铁量,如在“展望”部分描述的 TFR 抗体研究中所示。

Only recently, the roles of LCN2 and BDH2 have attracted attention in MDS and AML patients. LCN2 can bind to siderophores and thereby lead to iron internalization via endocytosis or to the secretion of iron via endosome recycling thereby potentially enabling iron overload or iron deficiency (). BDH2 catalyzes the rate-limiting step for the formation of the mammalian siderophore 2,5-dihydroxybenzoic acid (). This might facilitate LCN2-mediated iron uptake but also prevent iron overload in the cytoplasm and iron depletion in mitochondria. In cytogenetically normal AML patients, LCN2 mRNA was reduced (). Thereby, high LCN2 mRNA expression in the bone marrow was associated with a favorable outcome especially in combination with wild-type FLT3 showing an enhanced apoptosis under hydrogen peroxide and cytarabine treatment whereas showing a protective effect under DFO treatment. On the contrary, BDH2 overexpression has been associated with poor overall survival in cytogenetically normal AML () and with elevated ferritin levels as well as an increased risk for progression to leukemia in MDS (). As further mechanistical analyses are missing, it can only be speculated that in this case LCN2 overexpressing cells might have an increased LPI pool predisposing them to oxidative stress, whereas BDH2 overexpression might prevent cytoplasmatic iron overload. Further studies validating these results and unraveling the underling mechanisms are highly needed.
最近,LCN2 和 BDH2 在 MDS 和 AML 患者中的作用引起了关注。LCN2 可以结合铁载体,从而通过内吞作用导致铁的内化,或通过内体回收导致铁的分泌,从而可能导致铁过载或铁缺乏(67)。BDH2 催化了哺乳动物铁载体 2,5-二羟基苯甲酸形成的速率限制步骤(68)。这可能有助于 LCN2 介导的铁摄取,但也可以防止细胞质中的铁过载和线粒体中的铁耗竭。在细胞遗传学正常的 AML 患者中,LCN2 mRNA 减少(69)。因此,骨髓中高 LCN2 mRNA 表达与有利的预后相关,特别是与野生型 FLT3 结合,显示在过氧化氢和环磷酰胺处理下增强的细胞凋亡,而在 DFO 处理下显示保护作用。相反,BDH2 过表达与细胞遗传学正常的 AML 患者总生存率较低(70),以及铁蛋白水平升高以及 MDS 进展为白血病风险增加相关(71)。 由于缺乏进一步的机械分析,只能推测在这种情况下,LCN2 过表达的细胞可能具有增加的 LPI 池,使其易受氧化应激的影响,而 BDH2 过表达可能防止细胞质铁超载。迫切需要进一步研究来验证这些结果并揭示潜在机制。

The intracellular conversion of insoluble ferric to soluble ferrous iron is mediated by ferric reductases including STEAP protein members. Although STEAP1 has no iron reducing function, it co-localizes with transferrin and TFRC suggesting also a role in iron homeostasis. In AML, STEAP1 was shown to be overexpressed and associated with an adverse OS ().
胞内不溶性三价铁转化为可溶性二价铁是由包括 STEAP 蛋白成员在内的铁还原酶介导的。虽然 STEAP1 没有铁还原功能,但它与转铁蛋白和 TFRC 共定位,也暗示在铁稳态中起作用。在 AML 中,已经显示 STEAP1 被过度表达,并与不良 OS 相关。

Systemically elevated levels of the iron storage protein ferritin suggest a role for intracellular ferritin levels in MDS and AML as well. FTH1 was reported to be expressed particularly in erythroid blasts measured by immunohistochemistry (). In another study, FTH1 and FTL mRNA overexpression and FTH1 protein overexpression measured by immunoblot were shown in AML primary cells compared to peripheral mononuclear cells (). The presence of ferritin may reduce the LPI pool and therefore prevent ROS formation. In line with this, a decreased in vitro cytotoxic activity of cytarabine was detected in FTH1 overexpressing AML. Additionally, analyses of the erythroleukemia cell line K562 indicate that FTH1 expression might prevent ROS-induced protein misfolding () and ROS-induced activation of the HIF1A/CXCR4 pathway leading to an epithelial-to-mesenchymal transition (EMT)-like phenotype (). Besides, FTH1 might regulate RAF1 downregulation and activate pERK1/2 through downregulation of the expression of distinct microRNAs (). Therefore, intracellular ferritin expression might play a role in MDS and AML especially in erythroid blasts on many levels.
系统性升高的铁贮存蛋白铁蛋白水平表明细胞内铁蛋白水平在 MDS 和 AML 中也起作用。据报道,FTH1 在免疫组织化学检测中特别在红细胞前体细胞中表达(73)。在另一项研究中,与外周单核细胞相比,AML 原代细胞中显示了 FTH1 和 FTL mRNA 过表达以及通过免疫印迹检测到的 FTH1 蛋白过表达(9)。铁蛋白的存在可能减少 LPI 池,从而防止 ROS 形成。与此一致,检测到 FTH1 过表达的 AML 中细胞杂交素的体外细胞毒活性降低。此外,对红白血病细胞系 K562 的分析表明,FTH1 表达可能防止 ROS 诱导的蛋白质错误折叠(74),并防止 ROS 诱导的 HIF1A/CXCR4 通路激活,导致上皮-间质转化(EMT)样表型(75)。此外,FTH1 可能通过下调 RAF1 并通过下调不同 microRNA 的表达来激活 pERK1/2。因此,细胞内铁蛋白表达可能在 MDS 和 AML 中发挥作用,特别是在多个水平上的红细胞前体细胞中。

Expression of the iron exporter FPT is also suggested to reduce the LPI pool and thereby the formation of ROS. Low FPT levels in AML cells correlated with good risk cytogenetics, increased sensitivity to cytarabine treatment and favorable outcomes () but a causal relationship could not be deduced from this data.
铁出口蛋白 FPT 的表达也建议减少 LPI 池,从而减少 ROS 的形成。AML 细胞中低 FPT 水平与良好风险细胞遗传学、对阿糖胞苷治疗的增加敏感性和有利结果相关(10),但从这些数据中无法推断因果关系。

Overall, several changes in proteins associated with iron metabolism have been detected in MDS and AML cells. Mutually, the iron status and these proteins as well as several intracellular signaling pathways influence each other. Thereby, especially proteins directly regulating the intracellular iron pool seem to have an impact on cell viability and patient outcome.
总的来说,在 MDS 和 AML 细胞中检测到了与铁代谢相关的蛋白质的几处变化。铁状态和这些蛋白质以及几种细胞内信号传导途径相互影响。因此,特别是直接调节细胞内铁库的蛋白质似乎对细胞的存活能力和患者预后产生影响。

Iron and ROS Homeostasis in Leukemogenesis
白血病发生中的铁和 ROS 稳态

Iron and ROS homeostasis are closely entangled. Iron contributes to ROS formation by the production of hydroxyl radicals via the Haber-Weiss and Fenton reaction. Moreover, iron is involved in indirect ROS production. Multiple iron-containing enzymes and those which require iron as an indispensable cofactor contribute to ROS production under normal conditions (). So, as an important component of the respiratory chain iron is involved in the formation of mitochondrial ROS during oxidative phosphorylation (). Vice versa, ROS can interact with iron sulfur clusters ([4Fe-4S]), turning them into their inactive form ([3Fe-4S]+). This leads to a switch in the function of the iron-sulfur cluster protein ACO1 from its role as aconitase in the TCA cycle to its function as an IRE-binding protein regulating the expression of various proteins involved in iron metabolism and other pathways ().
铁和 ROS 稳态密切相关。铁通过 Haber-Weiss 和 Fenton 反应产生的羟基自由基促进 ROS 的形成。此外,铁参与间接 ROS 的产生。多种含铁酶和需要铁作为不可或缺辅因子的酶在正常条件下促进 ROS 的产生。因此,作为呼吸链的重要组成部分,铁参与了氧化磷酸化过程中线粒体 ROS 的形成。反之,ROS 可以与铁硫簇([4Fe-4S])相互作用,将其转化为其无活性形式([3Fe-4S]+)。这导致铁硫簇蛋白 ACO1 的功能发生转变,从其在 TCA 循环中的丙酮酸脱水酶角色转变为其作为 IRE 结合蛋白的功能,调节涉及铁代谢和其他途径的各种蛋白的表达。

Elevated ROS levels have been detected in MDS and AML patients compared to controls (, ). Moreover, iron overload is accompanied by increased ROS levels in this patient cohort (). Therefore, iron may contribute to leukemogenesis via its effect on the ROS homeostasis.
相对于对照组,MDS 和 AML 患者中检测到了升高的 ROS 水平(80, 81)。此外,铁过载伴随着该患者群体中 ROS 水平的增加(82-84)。因此,铁可能通过对 ROS 稳态的影响促进白血病发生。

Due to this connection, iron overload has been discussed to be involved in mutagenesis and leukemic transformation. Highly reactive hydroxyl radicals can directly interact with DNA leading to DNA damage (). Moreover, ROS can stimulate the generation of lipid peroxyl radicals especially of polyunsaturated fatty acids (PUFAs) leading to reactive aldehydes that are mutagenic and genotoxic (). In a mouse model for myelodysplastic syndrome using NUP98-HOXD13 (NHD13) transgenic mice, increased levels of ROS were detected in bone marrow nucleated cells accompanied by increased DNA double strand breaks supporting a connection between ROS and malignant transformation (). In this line, a 5-year prospective registry study including 599 MDS patients revealed a deceased rate of progression to AML in patients treated with iron chelators (). On the contrary, an earlier meta-analysis of Zeidan et al. did not confirm differences in the progression of MDS to AML with or without administration of iron chelators (). Thereby, analyses might differ due to different MDS subgroups, observation periods and a potential selection bias for patients with longer predicted survival receiving iron chelation. Deducing from these results, leukemic transformation as a result of iron overload is a valid hypothesis but data are still ambiguous and more prospective trials are required. Possibly, disease related risk factors in MDS may overcome the influence of iron overload on progression to AML. The fact that mutations in the hereditary hemochromatosis protein (HFE) have not been found to increase the risk of AML (, ) may also indicate that de novo AML development is not induced by systemic iron overload.
由于这种联系,铁过载被讨论涉及到突变和白血病转化。高度活性的羟基自由基可以直接与 DNA 相互作用,导致 DNA 损伤(85)。此外,ROS 可以刺激脂质过氧基自由基的生成,特别是多不饱和脂肪酸(PUFAs),导致具有突变原性和遗传毒性的反应性醛类(86)。在使用 NUP98-HOXD13(NHD13)转基因小鼠模型研究骨髓增生异常综合征时,发现骨髓核细胞中 ROS 水平升高,伴随着 DNA 双链断裂的增加,支持 ROS 与恶性转化之间的联系(87)。在这方面,一项包括 599 名 MDS 患者的 5 年前瞻性登记研究显示,接受铁螯合剂治疗的患者 AML 进展的死亡率降低(60)。相反,Zeidan 等人早期的荟萃分析并未证实 MDS 进展为 AML 时是否使用铁螯合剂有差异(88)。 因此,由于不同的 MDS 亚组、观察期和长期预测存活接受铁螯合治疗的患者可能存在潜在的选择偏倚,分析结果可能会有所不同。根据这些结果推断,铁过载导致白血病转化是一个有效的假设,但数据仍然模棱两可,需要更多前瞻性试验。可能,MDS 中与疾病相关的危险因素可能会克服铁过载对 AML 进展的影响。遗传性血色病蛋白(HFE)突变未被发现增加 AML 风险的事实(89, 90)也可能表明,系统性铁过载不会诱导新发 AML 的发展。

ROS is known to highly influence hematopoiesis including hematopoietic stem cell state and function (, ). ROS is also involved in the regulation of various intracellular processes and signaling pathways (e.g. NF-κB, MAPK, PI3K-Akt, ubiquitination) as it is able to interact directly with proteins, ions and other molecules (). Therefore, ROS might also influence stemness and proliferation of MDS and AML cells. Many molecular lesions related to MDS and AML development including mutations in FLT3, NRAS/KRAS and IDH1/2 affect intracellular ROS production, thus potentially promoting ROS-mediated oncogenic signaling (). Therefore, iron might impact intracellular signaling and cell fate decisions also by its influence on intracellular ROS signaling. Indeed, iron and associated proteins are involved in some of these signaling pathways as described in section Potential Roles of Iron-Related Intracellular Proteins in AML and MDS. However, studies further investigating this theory are needed.
ROS 被认为对造血过程产生高度影响,包括造血干细胞的状态和功能(91, 92)。ROS 还参与调节各种细胞内过程和信号通路(例如 NF-κB、MAPK、PI3K-Akt、泛素化),因为它能够直接与蛋白质、离子和其他分子相互作用(93)。因此,ROS 可能也会影响 MDS 和 AML 细胞的干性和增殖。许多与 MDS 和 AML 发展相关的分子病变,包括 FLT3、NRAS/KRAS 和 IDH1/2 的突变,影响细胞内 ROS 产生,从而潜在地促进 ROS 介导的致癌信号(94)。因此,铁可能通过影响细胞内 ROS 信号传导来影响细胞内信号传导和细胞命运决定。事实上,铁及其相关蛋白参与了一些这些信号通路,如《AML 和 MDS 中铁相关细胞内蛋白的潜在作用》部分所述。然而,需要进一步研究这一理论。

In the extreme, iron overload with subsequent overwhelming accumulation of ROS can lead to ferroptosis, a non-apoptotic form of programmed cell death dependent on iron that differs from other regulated cell death mechanisms as apoptosis. First labeled by Dixon in 2012, ferroptosis is the consequence of a reduced antioxidant defense leading to uncontrolled lipid peroxidation and subsequent oxidative cell death (). Depending on the activation of ROS-connected signaling pathways, cells are at a different risk for ferroptosis. Treatment of NRAS-Q61L mutated AML cells with the ferroptosis-inducing molecule erastin resulted in enhanced ROS levels and cytosolic translocation of HMGB1 leading to cell death, whereas this effect was not seen in unmutated cell lines (). Importantly, the effect was iron-dependent and HMGB1 knock-down lead to lower expression of TFRC.
在极端情况下,铁过载导致随后的 ROS 过度积累可能导致铁死亡,这是一种依赖于铁的非凋亡形式的程序化细胞死亡,与其他调节的细胞死亡机制如凋亡不同。由 Dixon 在 2012 年首次命名,铁死亡是抗氧化防御减少导致未受控制的脂质过氧化和随后的氧化细胞死亡的结果。根据 ROS 连接的信号通路的激活程度,细胞对铁死亡的风险不同。用诱导铁死亡分子 erastin 处理 NRAS-Q61L 突变的 AML 细胞导致 ROS 水平增加和 HMGB1 的胞浆转位导致细胞死亡,而在未突变的细胞系中未见到这种效应。重要的是,这种效应是依赖于铁的,HMGB1 敲除导致 TFRC 的表达降低。

Leukemic cells seem especially exposed to iron overload with the risk of undergoing ferroptosis. This indicates that they may have gained some ferroptosis evasion strategies. Indeed, Hole et al. could show that higher levels of NOX-derived ROS (ROS) in AML blasts were tolerated by evading oxidative stress response through suppression of p38MAPK signaling (). Additionally, glutathione peroxidases, which can protect cells from oxidative damage by reducing lipid hydroperoxides and free hydrogen peroxide are overexpressed in AML patient samples and associated with an adverse OS (). Moreover, Yusuf et al. show a dependency of murine and human AML cells on ALDH3A2, which can detoxify fatty aldehydes and thereby prevent oxidative damage due to lipid peroxidation (). In mouse models, reduction of Aldh3a2 induced ferroptosis in leukemic cells and was synergistically lethal combined with the inhibitor of glutathione peroxidase 4 (GPX4) RSL3, whereas it was dispensable for normal hematopoiesis. In this line, the transcription factor NFE2L2 also seems to strengthen the oxidative stress defense in leukemic cells by regulating the expression of many antioxidative proteins especially in case of additional chemotherapeutic treatment (, ). Parallelly, NFE2L2 also regulates the expression of iron-related proteins as FTH1, FTL and HMXO1 again supporting a close connection between ROS and iron homeostasis. All these findings support the hypothesis that AML cells might benefit from the toleration of higher iron and ROS levels. To which extent iron is involved in this pathomechanism and if this is also the case for MDS cells has to be further elucidated.
白血病细胞似乎特别容易受铁过载的影响,存在发生铁死亡的风险。这表明它们可能已经获得了一些铁死亡逃避策略。事实上,Hole 等人发现 AML 爆发细胞中 NOX 源 ROS(ROS)水平较高,通过抑制 p38MAPK 信号传导来规避氧化应激反应(97)。此外,谷胱甘肽过氧化物酶可以通过还原脂质过氧化物和游离过氧化氢来保护细胞免受氧化损伤,在 AML 患者样本中过度表达,并与不良 OS 相关(98)。此外,Yusuf 等人展示了小鼠和人类 AML 细胞对 ALDH3A2 的依赖性,ALDH3A2 可以解毒脂肪醛,从而防止由脂质过氧化引起的氧化损伤(99)。在小鼠模型中,减少 Aldh3a2 会导致白血病细胞发生铁死亡,并与谷胱甘肽过氧化物酶 4(GPX4)抑制剂 RSL3 联合使用具有协同致命作用,而对正常造血过程则是可有可无的。 在这一行中,转录因子 NFE2L2 似乎也通过调节许多抗氧化蛋白的表达,特别是在额外的化疗治疗情况下,加强了白血病细胞的氧化应激防御(100, 101)。与此同时,NFE2L2 还调节与铁相关的蛋白的表达,如 FTH1、FTL 和 HMXO1,再次支持 ROS 和铁稳态之间密切联系的假设。所有这些发现都支持 AML 细胞可能受益于对更高铁和 ROS 水平的耐受性的假设。铁在这一病理机制中的作用程度以及这是否也适用于 MDS 细胞,还需要进一步阐明。

Iron and the Microenvironment

Hematopoietic and leukemic blasts reside and proliferate in bone marrow niches interacting with their microenvironment. The microenvironment including mesenchymal cells, endothelial cells, sympathetic neurons, other hematopoietic and immune cells and the extracellular matrix is considered to be a key regulator of MDS and AML pathogenesis and recurrence (, ). Leukemic cells seem to adopt the bone marrow microenvironment according to their needs and suppress normal hematopoiesis via secretion of cytokines, microRNAs and exosomes.
造血和白血病原始细胞寄居并在骨髓微环境中增殖。微环境包括间质细胞、内皮细胞、交感神经元、其他造血和免疫细胞以及细胞外基质,被认为是 MDS 和 AML 发病和复发的关键调节因子。白血病细胞似乎根据自身需求采用骨髓微环境,并通过细胞因子、微 RNA 和外泌体的分泌抑制正常造血。

Excess iron in AML and MDS patients is deposited in various organs including the bone marrow thereby altering the composition of the hematopoietic niche and potentially leading to hematopoietic niche defects. A murine iron overload model revealed elevated ROS levels and increased bone resorption leading to changes in the bone microarchitecture with trabecular and cortical thinning of the bone (). This loss of bone substance seems related to changes in the bone marrow mesenchymal stem cells (BM-MSCs). Several alterations in the bone marrow stroma cell number and composition have been reported which concur in the fact that iron overload reduces the differentiation into osteoblasts relative to other cell subtypes and reduces matrix calcification (). Cheng et al. could also demonstrate a ROS-mediated cell death of mesenchymal cells due to iron overload mediated by the AMPK/MFF/DNM1L pathway triggering mitochondrial fragmentation and reducing ATP production (). The alterations of the mesenchymal cell compartment were also shown to influence their supporting function for hematopoiesis. Thereby, the expression of several adhesion molecules and cytokine secretion was altered in bone marrow stroma cells under overload conditions impairing their capacity to support hematopoietic cells growth (, , ). This might also be important for transplant engraftment during HSCT, as transplantation from normal donor mice to mice with iron overload resulted in a delayed hematopoietic reconstitution (). Therefore, the effects of iron overload on bone marrow structure and mesenchymal cells might attribute to the defective hematopoiesis found in MDS and AML patients.
AML 和 MDS 患者体内的过量铁被沉积在包括骨髓在内的各种器官中,从而改变造血微环境的组成,可能导致造血微环境缺陷。小鼠铁过载模型显示提高的 ROS 水平和增加的骨吸收,导致骨微结构发生变化,骨骼的梁状和皮质变薄(103)。这种骨质物质的流失似乎与骨髓间充质干细胞(BM-MSCs)的变化有关。已报道骨髓基质细胞数量和组成的多个改变,这些改变都表明铁过载减少了成骨细胞相对于其他细胞亚型的分化,并减少了基质钙化(103-105)。程等人还证明了一种 ROS 介导的细胞死亡,这是由于 AMPK/MFF/DNM1L 途径介导的铁过载引发了线粒体碎裂并减少了 ATP 产生(106)。已经显示,间充质细胞区的改变也影响了它们对造血的支持功能。 因此,在过载条件下,骨髓基质细胞中几种粘附分子的表达和细胞因子分泌发生改变,影响了它们支持造血细胞生长的能力(24, 105, 107)。这对于 HSCT 期间移植的移植结果可能也很重要,因为从正常供体小鼠到铁过载小鼠的移植导致造血重建延迟(107)。因此,铁过载对骨髓结构和间充质细胞的影响可能导致 MDS 和 AML 患者中发现的造血功能缺陷。

Macrophages in the bone marrow of MDS patients were shown to have higher FTH expression (). Additionally, expression of HMOX1 in macrophages was associated with an adverse patient outcome. In the microenvironment of solid tumors, tumor-associated macrophages (TAMs) are thought to contribute to tumor progression via delivery of iron to the tumor cells by an iron-release macrophage phenotype (). However, it has not been investigated if there might be a similar role of leukemia-associated macrophages.

Normal cells of the hematopoietic and especially erythropoietic system are also highly affected by changes in the iron homeostasis as already described in section Iron Homeostasis and its Role for Normal Hematopoiesis. Morbidity and mortality in iron overloaded MDS and AML patients might therefore largely be explained by the toxicity of iron to these cells. In a murine iron overload model using RUNX1S291fs-induced MDS mice, the survival of iron overloaded MDS mice decreased as a result of an impaired frequency and colony-forming capacity of normal hematopoietic stem cells ().
造血系统,尤其是红细胞生成系统的正常细胞也受铁稳态变化的影响,正如在铁稳态及其对正常造血作用部分所描述的那样。因此,铁过载的骨髓增生异常综合征(MDS)和急性髓系白血病(AML)患者的发病率和死亡率可能主要是由于铁对这些细胞的毒性所致。在使用 RUNX1S291fs 诱导的 MDS 小鼠铁过载模型中,铁过载的 MDS 小鼠的存活率降低,这是由于正常造血干细胞的频率和克隆形成能力受损所致。

The iron household in the bone marrow might also affect endothelial cells and the vascular architecture. Cellular iron deficiency increases VEGF-induced angiogenesis (, ). Moreover, it has been shown that ferritin promotes the assembly of endothelial cells by antagonizing the antiangiogenic effects of cleaved high molecular weight kininogen ().
骨髓中的铁家庭可能也会影响内皮细胞和血管结构。细胞铁缺乏增加了 VEGF 诱导的血管生成(111, 112)。此外,已经表明铁蛋白通过拮抗剪切高分子量激肽原的抗血管生成作用来促进内皮细胞的组装(113)。

Beside the bone marrow, an altered iron metabolism can also impact other organs. Iron overload due to multiple transfusions has been demonstrated to be toxic to various organs as liver, heart, pancreas, thyroid and pituitary gland leading to an increased morbidity and mortality (). The influence of organ iron overload on patient outcome in MDS and AML patients is not fully determined yet. As described in section Elevated Iron Levels in MDS and AML Patients, data on a potential correlation of liver iron overload with NRM are ambiguous.
除了骨髓外,改变的铁代谢也可能影响其他器官。由于多次输血导致的铁过载已被证明对肝脏、心脏、胰腺、甲状腺和垂体等各种器官具有毒性,导致患病率和死亡率增加。器官铁过载对 MDS 和 AML 患者预后的影响尚未完全确定。正如在 MDS 和 AML 患者中铁水平升高部分所述,关于肝脏铁过载与 NRM 之间潜在相关性的数据是模棱两可的。

Iron, Inflammation, and Infection

Iron and proteins related with iron overload are closely connected to local or systemic inflammation and might also influence the occurrence of infections by effects on the immune system and various pathogens.

Patients with AML and MDS are often immunocompromised due to a suppression of normal hematopoiesis by the disease and bone marrow toxicity of applied chemotherapies. Additionally, the patients frequently undergo multiple medical interventions including placements of catheters, which further increase the risk of inflammation and infection. Patients receiving an allogeneic HSCT have also a risk of inflammation due to a Graft-versus-Host Disease (GvHD) and need immunosuppressive therapy.
AML 和 MDS 患者常因疾病对正常造血功能的抑制和应用化疗药物的骨髓毒性而免疫功能受损。此外,患者经常接受多种医疗干预措施,包括置管术,这进一步增加了炎症和感染的风险。接受异基因造血干细胞移植的患者也存在由于移植物抗宿主病(GvHD)引起的炎症风险,并需要免疫抑制疗法。

Inflammatory stimuli lead to an upregulation of hepcidin and other acute-phase proteins as ferritin and caeruloplasmin as well as a down-regulation of negative acute-phase-proteins as transferrin. The resulting downregulation of available plasma iron may withhold iron from pathogenic microorganisms and protect healthy tissues from ROS damage at the site of infection. Many microorganisms require iron for electron transport, glycolysis, genome synthesis and defense, making it an essential nutrient. Excess iron has shown to stimulate the growth of many gram-positive and gram-negative bacteria, fungi and single-celled eukaryotes as well as the replication of viruses (, ). Correspondingly, patients with hemochromatosis or hemoglobinopathies are at increased risk for infectious diseases due to iron overload (, ).
炎症刺激导致肝铁蛋白和其他急性期蛋白(如铁蛋白和铜蓝蛋白)的上调,以及负急性期蛋白(如转铁蛋白)的下调。可用血浆铁的下调可能会阻止病原微生物获取铁,并保护健康组织免受感染部位的 ROS 损伤。许多微生物需要铁来进行电子传递、糖酵解、基因组合成和防御,使其成为一种必需营养素。过量的铁已被证明会刺激许多革兰氏阳性和革兰氏阴性细菌、真菌和单细胞真核生物的生长,以及病毒的复制。相应地,血色病或血红蛋白病患者由于铁过载而增加感染疾病的风险。

In patients undergoing allogeneic HSCT, high pre-transplant ferritin levels have been associated with an increased risk for invasive fungal pneumonia (, ) and hepatosplenic candidiasis (). Patients suffering from mucormycosis in allogeneic HSCT recipients were found to have a severe iron overload compared with a matched control population (). Moreover, early bacterial infections in allogeneic HSCT recipients were increased in patients with elevated pre-transplant hepcidin levels (). A large metanalysis demonstrated a higher incidence of blood stream infections, a lower incidence of chronic GvHD and no effect concerning acute GvHD to be associated with high-pretransplant ferritin levels (). Additionally, Pullarkat et al. reported in a prospective study, that iron overload measured by pre-transplant ferritin was a risk factor for mortality and blood stream infections but also for acute GvHD (). Thereby, all these studies point towards a prognostic impact of iron overload markers as ferritin and hepcidin for fungal and bacterial infections as well as for the occurrence of GvHD. Although an elevation of these markers was measured before the onset of the diseases, a bias for patients that were already initially prone to inflammation and infection cannot be excluded.
在接受同种异体造血干细胞移植的患者中,高于移植前铁蛋白水平与侵袭性真菌性肺炎(119, 120)和肝脾念珠菌病(121)的风险增加相关。与配对对照人群相比,同种异体造血干细胞移植受体中患有粘膜毛霉病的患者发现存在严重的铁超载(122)。此外,同种异体造血干细胞移植受体中早期细菌感染在具有升高的移植前肝铁蛋白水平的患者中增加(123)。一项大型荟萃分析显示,高于移植前铁蛋白水平与血流感染的发生率增加、慢性移植物抗宿主病发生率降低以及急性移植物抗宿主病无影响相关(52)。此外,Pullarkat 等人在一项前瞻性研究中报告,通过移植前铁蛋白测量的铁超载是死亡和血流感染的危险因素,也是急性移植物抗宿主病的危险因素(124)。因此,所有这些研究都指向铁超载标志物如铁蛋白和肝铁蛋白对真菌和细菌感染以及移植物抗宿主病的发生具有预后影响。 尽管在疾病发作之前测量到这些标记物的升高,但不能排除对那些最初就容易发炎和感染的患者存在偏见。

The function of cells belonging to the immune system may also be influenced by iron homeostasis. In MDS patients with iron overload measured by elevated ferritin and transferrin saturation, Chen et al. found a lower percentage of CD3+ T-cells and disrupted T-cell subsets accompanied by higher ROS-levels in these cells (). Using a murine iron overload model, Chen et al. showed that iron overload could reduce peripheral T-cells, decrease Th1/Th2 as well as Tc1/Tc2 ratio and increase CD4/CD8 ratio as well as the fraction of regulatory T-cells by inducing ROS-mediated oxidative stress and apoptosis of T-lymphocytes. The impact of these alterations on the anti-leukemic defense, inflammation and infection as well as patient outcome is yet unclear.
免疫系统细胞的功能也可能受铁稳态的影响。在通过升高的铁蛋白和转铁蛋白饱和度测量出的铁过载的 MDS 患者中,Chen 等人发现 CD3+ T 细胞的百分比较低,并伴随着这些细胞中较高的 ROS 水平。Chen 等人利用小鼠铁过载模型显示,铁过载可以减少外周 T 细胞,降低 Th1/Th2 以及 Tc1/Tc2 比率,并增加 CD4/CD8 比率以及调节性 T 细胞的比例,通过诱导 ROS 介导的氧化应激和 T 淋巴细胞的凋亡。这些改变对抗白血病防御、炎症和感染以及患者预后的影响尚不清楚。

Therapies Aiming at Iron Metabolism as a Possible Target in MDS and AML
针对 MDS 和 AML 中可能的靶点铁代谢的治疗方法

Features of iron overload, a differential iron metabolism and changes in proteins associated with iron have been found in MDS and AML patients. Markers of iron overload correlate with a worse prognosis in both patient cohorts. There is a rational for potential pathomechanisms explaining detrimental effects on the patient outcome by consequences of the altered iron metabolism. However, markers of iron overload are in many ways subject to the chicken-and-egg problem making it impossible to discriminate between cause and consequence. Therefore, interventional studies might cast light on the causative impact of the altered iron metabolism.
铁过载的特征,在 MDS 和 AML 患者中发现了不同的铁代谢和与铁相关的蛋白质的变化。铁过载的标志物与两组患者的预后不良相关。有一个合理的潜在病理机制来解释改变的铁代谢对患者结果的不利影响。然而,铁过载的标志物在许多方面都受到鸡生蛋问题的影响,这使得无法区分原因和后果。因此,干预性研究可能会揭示改变的铁代谢的原因性影响。

Iron-targeting strategies are based on the differential iron metabolism in case of MDS and AML compared to normal circumstances constituting a potential vulnerability in these diseases. Therapeutic strategies aiming at iron metabolism as a possible target in MDS and AML can be roughly distributed in four approaches: reduction of iron required for cellular functions via iron chelation, modulation of proteins involved in iron metabolism, induction of ferroptosis und exploitation of iron proteins for the delivery of antileukemic drugs ( Figure 3 ). Thereby, most studies have been conducted using iron chelators, whereas the other approaches are in the early stages of development.
铁靶向策略基于骨髓增生异常综合征(MDS)和急性髓系白血病(AML)相对于正常情况下的差异铁代谢,构成了这些疾病的潜在易感性。针对 MDS 和 AML 中铁代谢作为潜在靶点的治疗策略大致可分为四种方法:通过铁螯合减少细胞功能所需的铁、调节参与铁代谢的蛋白质、诱导铁死亡和利用铁蛋白传递抗白血病药物(图 3)。因此,大多数研究都是使用铁螯合剂进行的,而其他方法还处于早期开发阶段。

An external file that holds a picture, illustration, etc.
Object name is fimmu-11-627662-g003.jpg

Targets of different drugs interfering with iron metabolism. Simplified outline with colored arrows indicating the respective way of action. *loss of important protein functions can induce apoptosis and cell cycle arrest. excessive ROS production leading to lipid peroxidation can lead to ferroptosis. LCI, labile cellular iron; TFR, transferrin receptor.
不同药物干预铁代谢的靶标。带有彩色箭头的简化轮廓,指示各自的作用方式。*重要蛋白功能的丧失可能诱导凋亡和细胞周期停滞。 过量的 ROS 产生导致脂质过氧化,可能导致铁死亡。LCI,不稳定的细胞铁;TFR,转铁蛋白受体。

Iron Chelation 铁螯合

Iron overload, whether or not caused by an impaired underlying, dysregulated mechanisms or by multiple red blood cell transfusions, has been demonstrated to influence many intracellular and systemic processes. The reduction of iron overload thus seems like an obvious therapeutic strategy to correct prognostically unfavorable effects.

Chelators can bind metal ions and afterwards be excreted as water-soluble complexes. By reducing NTBI, LPI and LCI pools, iron chelators may influence enzyme functions depending on iron, and influence ROS homeostasis. Therefore, iron chelation therapy (ICT) offers a rational therapeutic option in the treatment of patients with iron overload aiming at an induction of an antileukemic effect and a reduction of secondary organ dysfunctions and infections. So far, there are three iron chelators approved by the European Commission/EMA for the treatment of patients with iron overload: Deferoxamine (DFO) administered parenterally and the orally available deferiprone (DFP) and deferasirox (DFX). Whereas DFP is approved only for patients with thalassemia major, DFO and DFX have broader indications including iron overload in MDS and AML patients.
螯合剂可以结合金属离子,随后以水溶性络合物的形式排泄出体外。通过减少非转铁蛋白铁(NTBI)、低分子量铁(LPI)和低分子量铁(LCI)库,铁螯合剂可能影响依赖铁的酶功能,并影响 ROS 稳态。因此,铁螯合疗法(ICT)为治疗铁过载患者提供了一种合理的治疗选择,旨在诱导抗白血病效应并减少继发性器官功能障碍和感染。到目前为止,欧洲委员会/EMA 已批准了三种铁螯合剂用于治疗铁过载患者:经肠道给予的去铁胺(DFO)和口服可用的去铁酮(DFP)和去铁酸(DFX)。DFP 仅适用于重型地中海贫血患者,而 DFO 和 DFX 具有更广泛的适应症,包括 MDS 和 AML 患者的铁过载。

Iron chelators seem to act by various mechanisms. Deferoxamine (DFO) was shown to negatively affect DNA synthesis and reduce cell growth in the leukemic cell line K562 by impairing the activity of ribonucleotide reductase (). Ribonucleotide reductase catalyzes the formation of deoxyribonucleotides and needs iron as a cofactor to build a tyrosyl radical crucial for its function. DFO was shown to inhibit the enzyme activity by depletion of the LCI pools necessary to regenerate the active enzyme (). Moreover, iron chelators can affect ROS homeostasis in two opposite directions leading to either ROS depletion or ROS promotion (). The ROS depleting effect is suggested to depend on diminished free labile iron levels (), whereas the ROS promoting effect may be facilitated by an iron-mediated free radical generation through the iron-chelator-complex (, ) or by a potentially iron-unrelated induction of ROS signaling (). The effect of ICT on ROS seems thereby to depend on the binding-characteristics of the chelator, the time of treatment and the used concentration (). Both mechanisms seem to play a role in ICT activity. The ROS-promoting activity has been suggested to participate in the effect of DFX in AML cells (, ). On the contrary, oxidative stress was reduced under long-term DFX treatment in MDS patients with iron overload (, ). ICT is also reported to enhance the effect of other antiproliferative drugs. In vitro and in vivo studies showed an increased antileukemic effect for the combination of DFO and cytarabine (), DFX and decitabine () as well as DFO and doxorubicin (). A potential mode of action for the combination of DFX with doxorubicin might be an increase of the intracellular calcium resulting in an improved sensitivity to chemotherapy in leukemia cell lines (). Moreover, ICT has been found to modulate different signaling pathways including a repression of mTOR and NF-kB signaling pathways, which might also explain a potential synergistic effect with other drugs (, ). Iron chelators were also shown to act synergistically with differentiating agents in the treatment of AML (). Thereby, iron chelation led to ROS production, activation of MAPK pathways and also induced expression and phosphorylation of the vitamin D3 receptor (VDR) leading to blast differentiation in vitro, in vivo and also in one patient with secondary AML treated with DFX and vitamin D3 after relapse of the disease (). Deducing from these results, the mechanism of ICT action might not solely be the iron-deprivation but rather also a modulation of ROS homeostasis and intracellular signaling. A relation of the latter effects with the iron-modulating activity seems likely, but iron-independent effects of the ICT cannot be excluded. The diverse effects might not only depend on the way of chelator administration but also on the status of the treated cells.
铁螯合剂似乎通过各种机制起作用。已经证明,去氧鞘氨醇(DFO)通过损害核糖核苷酸还原酶的活性(126)而在白血病细胞系 K562 中负面影响 DNA 合成并减少细胞生长。核糖核苷酸还原酶催化去氧核糖核苷酸的形成,并需要铁作为辅因子来构建对其功能至关重要的酪氨酸基自由基。已经证明,DFO 通过耗尽再生活性酶所需的 LCI 池来抑制酶活性(127)。此外,铁螯合剂可以以两个相反的方向影响 ROS 稳态,导致 ROS 耗竭或 ROS 促进(128)。据推测,ROS 耗竭效应取决于降低的游离活性铁水平(129),而 ROS 促进效应可能通过铁介导的自由基生成(通过铁螯合剂复合物)(130, 131)或通过潜在的与铁无关的 ROS 信号诱导(132)来促进。因此,ICT 对 ROS 的影响似乎取决于螯合剂的结合特性、处理时间和使用浓度(133)。这两种机制似乎在 ICT 活性中起作用。 ROS 促进活性被认为参与了 DFX 在 AML 细胞中的作用(128, 133)。相反,在铁过载的 MDS 患者中,长期 DFX 治疗下氧化应激减少(134, 135)。ICT 也被报道能增强其他抗增殖药物的效果。体外和体内研究显示,联合应用 DFO 和阿糖胞苷(136)、DFX 和地西他滨(137)以及 DFO 和阿霉素(138)具有增强的抗白血病效果。DFX 与阿霉素联合作用的潜在作用模式可能是增加细胞内钙浓度,从而提高白血病细胞对化疗的敏感性(138)。此外,ICT 已被发现调节不同的信号通路,包括抑制 mTOR 和 NF-kB 信号通路,这也可能解释了与其他药物的潜在协同作用(139, 140)。铁螯合剂还显示出与分化剂在 AML 治疗中协同作用的效果(133)。 因此,铁螯合导致 ROS 产生,激活 MAPK 途径,并诱导维生素 D3 受体(VDR)的表达和磷酸化,在体外、体内以及一名患有继发性 AML 的患者中,该患者在疾病复发后接受 DFX 和维生素 D3 治疗,从而导致了爆炸分化(133)。从这些结果推断,ICT 作用的机制可能不仅仅是铁剥夺,而且还可能是 ROS 稳态和细胞内信号传导的调节。后者效应与铁调节活性的关系似乎很可能存在,但 ICT 的铁独立效应不能被排除。这些多样的效应可能不仅取决于螯合剂的给药方式,还取决于受治疗细胞的状态。

Clinically, there is some evidence from post-hoc analyses in cohorts of low/intermediate-1 risk MDS patients with iron overload that iron chelators as DFX may improve hematological parameters after administration over at least one year in a small proportion of the patients (). An increase of hemoglobin, platelets and/or neutrophils was observed in 11%–22% of the patients with a few multilineage improvements and a few transfusion independencies. Thereby, the data of List et al. suggest a possible correlation between the amount of ferritin reduction by iron chelators and hematological response (). In a retrospective analysis of 182 patients with MDS with various subtypes, the multivariate analysis revealed a significant benefit in OS for patients receiving ICT with 140.9 months vs 36.3 months (p=0.0008) in case of refractory anemia (RA or, according to the present WHO classification: MDS-RS), 133.4 months vs 73.3 months (p=0.02) in case of refractory anemia with ring sideroblasts (RARS/RARS-t, corresponding to MDS-RS according to the present WHO classification) and no difference for refractory cytopenia with multilineage dysplasia (RCMD/RCMD-RS, corresponding to MDS-MLD according to the present WHO classification) (). The latter indicates that not all subtypes of MDS may benefit from ICT. It should also be noted that ICT seems to have the largest effects in subtypes which were suspected to suffer more from primary iron overload, MDS-RS and MDS-RA but not MDS-MLD, as marked by a reduced hepcidin/ferritin ratio described in section Elevated Iron Levels in MDS and AML Patients.
在临床上,有一些证据表明,在低/中等-1 风险 MDS 患者的队列后分析中,铁过载患者的铁螯合剂 DFX 可能在至少一年的治疗后改善一小部分患者的血液学参数(141-145)。在 11%-22%的患者中观察到血红蛋白、血小板和/或中性粒细胞的增加,其中有少数多系细胞改善和少数输血独立性。因此,List 等人的数据表明,铁螯合剂通过减少铁蛋白的数量可能与血液学反应存在可能的相关性(143)。在对 182 名不同亚型 MDS 患者进行的回顾性分析中,多变量分析显示,接受 ICT 治疗的患者的 OS 获益显著,分别为 140.9 个月与 36.3 个月(p=0.0008)(对于难治性贫血(RA)或根据目前的 WHO 分类为 MDS-RS),133.4 个月与 73.3 个月(p=0.02) 对于伴有环状铁斑细胞的难治性贫血(RARS/RARS-t,根据当前 WHO 分类对应于 MDS-RS),以及对于多系发育异常的难治性细胞减少症(RCMD/RCMD-RS,根据当前 WHO 分类对应于 MDS-MLD)没有差异(146)。后者表明,并非所有 MDS 亚型都能从 ICT 中受益。还应注意的是,ICT 似乎对于那些被怀疑更容易受到原发性铁过载影响的亚型效果最大,如 MDS-RS 和 MDS-RA,而不是 MDS-MLD,这在 MDS 和 AML 患者铁水平升高部分中所描述的降低肝铁蛋白/铁蛋白比率中有所体现。

A recent systematic review and meta-analysis by Zeidan et al. included nine studies (4 prospective and 5 retrospective) with a total of 2450 patients with particularly low-risk MDS of whom 38.4% received ICT (). Patients with ICT had a lower mortality and longer OS compared to no ICT with a pooled estimate of the ratio median OS of 2.1 years, suggesting that iron chelation therapy might double the OS in MDS. Additionally, there were some hints at a correlation between dose intensity of ICT and OS. Two of the reported studies compared patients with high adequate ICT to no ICT showing a highly significant survival advantage for patients with a higher adequate dose, but comparing any degree of ICT with no ICT, the OS benefit was less pronounced (, , ). In the study by Rose et al., adequate ICT was associated with median OS of 124 months compared to 85 months for ICT (p < 0.001) (). Similar results were described by Delforge regarding OS with adequate ICT and no adequate ICT (p = 0.001) but not between weak ICT and no ICT (). Hereby, adequate chelation was defined for DFO subcutaneously (40 mg/kg/day in slow infusion over 8–12 h for at least 3 days per week), DFX (20–30 mg/kg/day p.o.) or DFP (30–75 mg/kg/day p.o.); weak chelation treatment was considered to be less than 3 g per week of DFO. The question whether there are any differences regarding the efficacy between the iron chelators cannot be answered finally due to a lack of randomized trials. However, the compliance of DFX might be better than that of DFO or DFP due to the oral mode of administration and the less frequent occurrence of side effects resulting in a continued application and more remarkable reduction of iron overload (). Gastrointestinal adverse events and neutropenia were more frequently observed in DFP than in DFO (, ).
Zeidan 等人最近进行的系统回顾和荟萃分析包括了 9 项研究(4 项前瞻性和 5 项回顾性),共涉及 2450 名特别低风险 MDS 患者,其中 38.4%接受了铁减毒疗法(ICT)。接受 ICT 的患者与未接受 ICT 的患者相比,死亡率较低,生存期较长,中位 OS 比值的综合估计为 2.1 年,表明铁减毒疗法可能会使 MDS 患者的 OS 翻倍。此外,有一些迹象表明 ICT 的剂量强度与 OS 之间存在相关性。报道的两项研究中,将接受高适当 ICT 的患者与未接受 ICT 的患者进行比较,结果显示高适当剂量患者具有明显的生存优势,但将任何程度的 ICT 与未接受 ICT 进行比较时,OS 的益处不那么显著。在 Rose 等人的研究中,适当的 ICT 与 ICT 相比,中位 OS 分别为 124 个月和 85 个月(p < 0.001)。Delforge 关于适当 ICT 和非适当 ICT 之间的 OS 也描述了类似的结果(p = 0.001),但在弱 ICT 和未接受 ICT 之间没有明显差异。 在此,为 DFO 皮下适当螯合治疗被定义为(每周至少 3 天,40 毫克/千克/日缓慢输注 8-12 小时),DFX(20-30 毫克/千克/日口服)或 DFP(30-75 毫克/千克/日口服);弱螯合治疗被认为是每周少于 3 克的 DFO。由于缺乏随机试验,目前无法最终回答关于铁螯合剂之间疗效差异的问题。然而,由于口服给药方式和副作用发生频率较低,DFX 的依从性可能比 DFO 或 DFP 更好,从而导致持续应用和更显著的铁超载减少(149-153)。与 DFO 相比,DFP 中更频繁观察到胃肠道不良事件和中性粒细胞减少症(149, 150)。

Randomized trials in MDS looking for the clinical benefit using iron chelators in patients with excessive iron overload are highly needed. Recently, Angelucci et al. published data from the randomized clinical study TELESTO (). Here, 225 patients with low- to intermediate-1 risk MDS were treated with DFX versus placebo in a 2:1 randomization. The event-free survival (EFS) was prolonged with 3.9 years in the DFX versus 3.0 years in the placebo arm (HR 0.64). Although the study is limited by an amendment from a planned phase 3 trial with 630 patients to a phase 2 trial with 225 patients and different follow-up times between the groups, the data again support a benefit of iron chelation on the clinical outcome.
MDS 中寻找使用铁螯合剂治疗铁过载患者的临床益处的随机试验非常需要。最近,Angelucci 等人发表了来自随机临床研究 TELESTO(154)的数据。在这项研究中,225 名低至中度 1 风险 MDS 患者接受了 DFX 与安慰剂的 2:1 随机分组治疗。DFX 组的无事件生存期(EFS)延长了 3.9 年,而安慰剂组为 3.0 年(HR 0.64)。尽管该研究受到计划中的拟进行的包括 630 名患者的 3 期试验修正为包括 225 名患者的 2 期试验以及组间不同的随访时间的限制,但数据再次支持铁螯合对临床结果的益处。

There are some weak hints that iron chelation also has positive effects after allogeneic HSCT on hematological reconstitution, but the number of patients reported is limited. So, in a rather small cohort of eight patients with incomplete hematological reconstitution after allogenic HSCT, treatment with DFX led to hematological improvements with a subsequent loss of transfusion dependency in all patients within a maximum of 30 days (). Moreover, Cho et al. propose an enhanced graft-versus-leukemia (GvL) effect leading to a lower incidence of relapse, an improvement of DFS and OS, while the incidence of chronic GvHD by DFX treatment post-transplant increases (). The data, however, are limited due to their retrospective analysis.
有一些微弱的迹象表明,在同种异体造血干细胞移植(HSCT)后,铁螯合也对血液再生有积极影响,但报道的患者数量有限。因此,在一个相当小的队列中,8 名同种异体 HSCT 后血液再生不完全的患者中,使用脱铁胺(DFX)治疗导致血液学改善,在最多 30 天内所有患者都不再需要输血(155)。此外,Cho 等人提出,DFX 治疗后增强了移植物抗白血病(GvL)效应,导致复发率降低,DFS 和 OS 改善,而移植后 DFX 治疗导致慢性 GvHD 的发生率增加(156)。然而,由于其回顾性分析,数据有限。

Besides the iron chelators mentioned above, there are also new iron chelators and other substances with iron-chelating properties under investigation. In a phase 2 study, triapine, forming a potentially redox active iron complex and known to inhibit the M2 subunit of the ribonucleotide reductase, showed clinical activity when administered sequentially with fludarabine in patients with accelerated myeloproliferative diseases and secondary AML (, ). Ciclopirox olamine, an antimycotic agent with iron chelation activity, showed a hematologic improvement in 2 out of 23 patients with relapsed or refractory hematologic diseases in a phase 1 study (). Moreover, eltrombopag, a thrombopoietin receptor agonist approved for the treatment of idiopathic thrombocytopenic purpura and aplastic anemia, has also shown to be an efficient iron chelator, mobilizing iron and reducing ROS working synergistically with other iron chelators in vitro (). In a mechanistic study on HSCs, eltrombopag stimulated hematopoiesis at the stem cell level through iron chelation-mediated reprogramming (). Randomized placebo-controlled phase 1/2 data revealed a reduction of clinically relevant thrombocytopenic events upon eltrombopag treatment in MDS and AML patients (, ). On the contrary, a subsequent randomized phase 2 trial investigated the receipt of eltrombopag during standard induction therapy in AML patients and found no clinical benefit of eltrombopag but rather a tendency for increased severe adverse events ().
除了上述提到的铁螯合剂外,还有新的铁螯合剂和其他具有螯合铁特性的物质正在调查中。在一项 2 期研究中,三氮唑啉(triapine)与氟达拉滨(fludarabine)顺序给药时,在加速性骨髓增生疾病和继发性 AML 患者中显示出临床活性,形成潜在的氧化还原活性铁络合物并已知抑制核糖核苷酸还原酶 M2 亚基(157, 158)。环丙沙星醇胺(ciclopirox olamine)是一种具有铁螯合活性的抗真菌药物,在一项 1 期研究中,对 23 名复发或难治性血液疾病患者中的 2 名患者显示出血液学改善(159)。此外,厄洛替尼(eltrombopag)是一种治疗特发性血小板减少性紫癜和再生障碍性贫血的血小板生成素受体激动剂,也显示出是一种有效的铁螯合剂,在体外与其他铁螯合剂协同作用,促进铁的转运并减少 ROS(160)。在对 HSCs 的机制研究中,厄洛替尼通过铁螯合介导的重编程刺激干细胞水平的造血(161)。 随机安慰剂对照的 1/2 期数据显示,在 MDS 和 AML 患者中,使用厄洛替尼治疗可减少临床相关的血小板减少事件(162, 163)。相反,随后进行的随机 2 期试验调查了 AML 患者在标准诱导治疗期间接受厄洛替尼的情况,发现厄洛替尼并没有临床益处,反而有增加严重不良事件的趋势(164)。

The clinical data demonstrate activity of ICT in the treatment of low/intermediate-1 risk MDS patients with iron overload suggesting a potency of ICT as an additional treatment option. The other way around, it can be deduced that iron overload in these patients might be accountable for a worse patient outcome. Thereby, ICT seems to specifically improve the hematopoietic response. There is only limited data on the effect of ICT on leukemic cells themselves and on the role of ICT in AML. Deducing from some preclinical studies, ICT might here influence intracellular signaling and ROS homeostasis specifically in combination with other drugs.
临床数据显示,对于铁过载的低/中风险 MDS 患者,ICT 在治疗中显示出活性,表明 ICT 作为一种额外的治疗选择具有潜力。反过来,可以推断这些患者的铁过载可能导致患者预后较差。因此,ICT 似乎能够特别改善造血反应。关于 ICT 对白血病细胞本身的影响以及 ICT 在 AML 中的作用,目前只有有限的数据。从一些临床前研究推断,ICT 可能会影响细胞内信号传导和 ROS 稳态,特别是与其他药物结合使用时。

Modulation of Proteins Involved in Iron Metabolism

Many different proteins are involved in iron metabolism and have demonstrated differential expression in MDS and AML cells as described in section Potential Roles of Iron-Related Intracellular Proteins in AML and MDS. Targeting these proteins therefore represents another potential treatment approach.
许多不同的蛋白质参与铁代谢,并在 MDS 和 AML 细胞中表现出差异表达,如在《AML 和 MDS 中铁相关细胞内蛋白质的潜在作用》一节中所述。因此,瞄准这些蛋白质代表了另一种潜在的治疗方法。

Considering that malignant cells need iron for proliferation and that TFR was demonstrated to be expressed on the surface of AML cells, it was tested if inhibition of the TFR may lead to an antiproliferative effect due to a decreased iron import. Indeed, various TFR antibodies showed inhibition of DNA synthesis and a subsequent growth inhibition of AML cells in vitro and a reduction of tumor growth in mouse models (, ). The effect of different TFR antibodies was even enhanced when used in combination (). However, as TFR is also expressed on normal cells of the hematopoietic system and TFR antibodies have shown to impair growth of normal hematopoietic cells as well (), bone marrow toxicity is thought to be an important side effect of the treatment. Despite this fact, administration of the TFR antibody 42/6 in patients with refractory cancer including lymphoma patients was well tolerated in a phase 1 trial (). Clinical data for the treatment of MDS and AML patients are missing.
考虑到恶性细胞需要铁来增殖,并且已经证明 TFR 在 AML 细胞表面表达,因此测试了抑制 TFR 是否会导致抗增殖效应,因为铁的进口减少。确实,各种 TFR 抗体在体外抑制了 DNA 合成,并导致 AML 细胞的后续生长抑制以及小鼠模型中肿瘤生长的减少(126, 165–168)。当不同 TFR 抗体结合使用时,甚至可以增强其效果(169)。然而,由于 TFR 也在造血系统的正常细胞上表达,并且 TFR 抗体已经显示出对正常造血细胞的生长有损害作用(165),因此骨髓毒性被认为是治疗的一个重要副作用。尽管如此,TFR 抗体 42/6 在包括淋巴瘤患者在内的难治性癌症患者中的Ⅰ期试验中耐受良好(170)。缺乏治疗 MDS 和 AML 患者的临床数据。

Hepcidin as regulator of systemic iron provides another reasonable antileukemic target with the aim to reduce overall iron load and subsequent toxic effects on organs as heart, liver and bone marrow. Hepcidin as a potential target of iron-homeostasis has been investigated in iron overload situations but without specific data for MDS and AML. Synthetic hepcidin mimetics such as PTG-300 or LJPC-401 have been reported to reduce serum iron levels and to be well-tolerated in phase 1 trials in healthy subjects and patients with iron overload, although the clinical relevance has still to be determined in ongoing studies (, ). Various other hepcidin targeting agents, for instance humanized monoclonal antibodies (LY2787106; 12B9m), the anticalin (PRS-080), and Lexaptepid Pegol (NOX-H94) have been tested in preclinical models or early in-human trials as reviewed by Crielaard et al., but failed major efficacy so that further development was stopped (). Matripase-2 (MT2A), a transmembrane serine protease predominantly expressed in hepatocytes suppresses the expression of hepatic hepcidin by cleaving the membrane hemojuvelin into an inactive form (). Antisense DNA (IONIS-TMPRSS6-LRx) or liposomal siRNA (ALN-TMP) as well as some protease inhibitors have demonstrated specific MT-2 inhibiting activity with the potential to reduce secondary anemia in patients with iron overload in preclinical models (). Targeting the hepcidin-ferroportin pathway by inhibiting the bone morphogenic protein BMP6, which stimulates hepcidin expression in the liver or the iron exporter ferroportin via the monoclonal antibodies, LY3113593 and LY2928057, has not been further investigated beyond a phase 1 study (). Therefore, data on the role of the hepcidin-ferroportin axis as a potential therapeutic target were mostly negative, further studies of MT-2 inhibitors have to be awaited.
Hepcidin 作为系统铁的调节因子,提供了另一个合理的抗白血病靶点,旨在减少整体铁负荷并减少对心脏、肝脏和骨髓等器官的毒性影响。 Hepcidin 作为铁稳态的潜在靶点已在铁过载情况下进行了研究,但对 MDS 和 AML 没有具体数据。合成 hepcidin 类似物,如 PTG-300 或 LJPC-401 据报道可降低血清铁水平,并在健康受试者和铁过载患者的 1 期试验中耐受良好,尽管临床相关性仍需在进行中的研究中确定。其他各种针对 hepcidin 的药物,例如人源化单克隆抗体(LY2787106; 12B9m)、抗卡林(PRS-080)和 Lexaptepid Pegol(NOX-H94)已在预临床模型或早期人体试验中进行了测试,如 Crielaard 等人所述,但未能取得重大疗效,因此进一步开发被中止。Matripase-2(MT2A)是一种跨膜丝氨酸蛋白酶,主要在肝细胞中表达,通过将膜型血红蛋白切割成无活性形式,抑制肝 hepcidin 的表达。 反义 DNA(IONIS-TMPRSS6-LRx)或脂质体 siRNA(ALN-TMP)以及一些蛋白酶抑制剂已经在临床前模型中表现出特异性 MT-2 抑制活性,有潜力减少铁过载患者的继发性贫血(173-176)。通过抑制骨形态发生蛋白 BMP6 靶向肝脏中刺激 hepcidin 表达的途径或通过单克隆抗体 LY3113593 和 LY2928057 靶向铁输出蛋白 ferroportin,尚未进一步研究超出第 1 阶段研究(177)。因此,关于 hepcidin-ferroportin 轴作为潜在治疗靶点的数据大多为负面,对 MT-2 抑制剂的进一步研究仍需等待。

Induction of Ferroptosis 诱导铁死亡

In contrast to influencing the course of the disease in MDS and AML by reducing iron overload, enhancing iron overload to induce ferroptosis represents an opposing but alterative mechanism. There are various agents acting as inhibitors or inducers of ferroptosis: Iron chelators, lipophilic antioxidants, inhibitors of lipid peroxidation and depletion of PUFAs inhibit ferroptosis, whereas ferroptosis is induced by the accumulation of iron or PUFA-phospholipids and by the depletion of endogenous inhibitors such as GSH, NADPH, GPX4 or vitamin E ().
与通过减少铁过载影响 MDS 和 AML 疾病进程不同,增强铁过载以诱导铁死亡代表了一种相反但可替代的机制。有各种药物作为铁死亡的抑制剂或诱导剂:铁螯合剂、亲脂抗氧化剂、脂质过氧化抑制剂和 PUFA 耗竭抑制铁死亡,而铁死亡则是通过铁或 PUFA-磷脂的积累以及内源性抑制剂(如 GSH、NADPH、GPX4 或维生素 E)的耗竭来诱导的(178)。

Erastin is a ferroptosis inducer acting on multiple levels. It inhibits the cysteine/glutamate antiporter system Xc-, thereby revoking cysteine import and thus reducing glutathione synthesis. It activates TP53, which can also inhibit system Xc, and it induces the opening of voltage-dependent anion channels (VDACs), thereby inducing mitochondrial dysfunction (). The activation of ferroptosis by erastin promotes chaperone-mediated autophagy and the degradation of glutathione peroxidase 4 (GPX4) (). In AML cell lines, erastin has shown a dose-dependent mixed-type of cell death, including ferroptosis, and enhanced the antileukemic effect of cytarabine and doxorubicin (). Besides, the tyrosine kinase inhibitor sorafenib, which is approved for the treatment of liver renal and thyroid carcinoma and also showed efficacy in AML patients with FLT3-ITD (, ), also inhibits the system Xc- ().
Erastin 是一种作用于多个水平的铁死亡诱导剂。它抑制半胱氨酸/谷氨酸抗体转运蛋白系统 Xc-,从而撤销半胱氨酸的进口,从而减少谷胱甘肽的合成。它激活 TP53,TP53 也可以抑制系统 Xc,并诱导电压依赖性的膜通道(VDACs)的开放,从而诱导线粒体功能障碍。Erastin 通过激活铁死亡促进分子伴随自噬和谷胱甘肽过氧化物酶 4(GPX4)的降解。在 AML 细胞系中,Erastin 显示出一种剂量依赖的混合型细胞死亡,包括铁死亡,并增强了紫杉醇和阿霉素的抗白血病效果。此外,已获批用于治疗肝肾和甲状腺癌的酪氨酸激酶抑制剂索拉非尼,也在 FLT3-ITD 阳性 AML 患者中显示出疗效,同时也抑制系统 Xc。

Other ferroptosis inducers have shown antileukemic activity in AML cells as well: Dihydroartemisinin (DHA) was shown to induce ferroptosis of AML cells by leading to accelerated degradation of ferritin and increasing LPI (). Besides, the frequently used antileukemic drug decitabine has recently suggested to induce ferroptosis (). Treatment of MDS/AML cell lines with decitabine increased ROS levels by reducing GSH and GPX4 activity. Ferroptosis inducers enhanced the effect of decitabine, whereas ferroptosis inhibitors abrogated the effect. As iron chelators also potentiated the effect of decitabine, this is another hint that treatment effects may be mediated by ROS and might also be influenced by the intracellular iron household.
其他诱导铁死亡的物质在 AML 细胞中也显示出抗白血病活性:二氢青蒿素(DHA)被证明通过加速降解铁蛋白和增加 LPI 来诱导 AML 细胞的铁死亡。此外,常用的抗白血病药物地西他滨最近也被认为能诱导铁死亡。用地西他滨处理 MDS/AML 细胞系会通过降低 GSH 和 GPX4 活性增加 ROS 水平。铁死亡诱导剂增强了地西他滨的效果,而铁死亡抑制剂则消除了效果。由于铁螯合剂也增强了地西他滨的效果,这是另一个暗示治疗效果可能通过 ROS 介导,并且也可能受细胞内铁离子家庭的影响的线索。

The data suggest a potential use of ferroptosis inducers in the treatment of AML, although clinical data are missing. There are not enough data to estimate the role of ferroptosis induction in MDS.
数据表明,虽然临床数据缺失,但富死亡诱导剂在治疗 AML 中可能具有潜在用途。没有足够的数据来评估富死亡诱导在 MDS 中的作用。

Exploitation of Iron Proteins for Targeted Drug Delivery

Another attempt to specifically target malignant cells is to use the TFR as target protein for the delivery of another tumor-specific cargo. Covalent conjugates of the ferroptosis inducing agent artemisinin and a transferrin-receptor targeting peptide combined ferroptosis induction and targeted delivery and revealed antileukemic affectivity in vitro (). Thereby, artemisinin could be co-internalized with receptor-bound transferrin and could use the iron deliberated by transferrin to generate cytotoxic ROS. Moreover, transferrin-conjugated nanoparticles have shown potential in the delivery of antileukemic drugs: Transferrin-conjugated lipid nanoparticles delivering an antisense oligonucleotide targeting BCL2 mRNA induced caspase-dependent apoptosis in AML cell lines and suppressed tumor growth of human AML xenograft tumors in mice (, ). Transferrin-conjugated liposomal nanoparticles containing antagomiR-126 resulted in reduction of leukemic stems cells in an AML mouse model (). Additionally, transferrin-conjugated nanoparticles delivering doxorubicin showed cytotoxicity in myeloid leukemia cells in vitro and in vivo (, ). Also, transferrin-conjugated polymeric nanoparticles delivering edelfosine and lipid-based nanoparticles delivering etoposide revealed antileukemic activity in vitro (, ).
另一个专门针对恶性细胞的尝试是利用转铁蛋白受体作为另一种肿瘤特异性载体的靶蛋白。靶向肽与诱导铁死亡剂青蒿素的共价结合物结合,结合了铁死亡诱导和靶向传递,在体外显示出抗白血病作用(186)。因此,青蒿素可以与受体结合的转铁蛋白一起内吞,并利用转铁蛋白释放的铁来产生细胞毒性 ROS。此外,转铁蛋白结合的纳米颗粒在抗白血病药物的传递中显示出潜力:转铁蛋白结合的脂质纳米颗粒传递靶向 BCL2 mRNA 的反义寡核苷酸在 AML 细胞系中诱导依赖半胱氨酸蛋白酶的凋亡,并抑制小鼠 AML 异种移植瘤的肿瘤生长(187, 188)。转铁蛋白结合的脂质体纳米颗粒含有抗 miR-126,导致 AML 小鼠模型中白血病干细胞的减少(189)。此外,转铁蛋白结合的纳米颗粒传递阿霉素在体内外显示出对骨髓性白血病细胞的细胞毒性(190, 191)。 此外,转铁蛋白结合的聚合物纳米颗粒传递依达福辛和传递依托泊苷的脂质基纳米颗粒在体外显示出抗白血病活性(192, 193)。

Ferritin can also be used as a protein cage for the delivery of other molecules due to its tertiary structure (). As FTH can be bound and uptaken by TFRC (), this provides another way of directed targeting. Ferritin nanovesicles delivering cytochrome C induced apoptosis in a promyelocytic AML cell line (). Delivery of cytarabine in form of Fe3O4@SiO2-cytarabine nanoparticles increased the cytotoxic effect of cytarabine alone about two orders of magnitude in cell lines (). The combination of erastin and rapamycin, an inducer of autophagy, with ferritin as a nanodrug showed increased inhibition of tumor growth compared to the drugs administered separately (). Besides, use of iron saturated ferritin as a component of nanoparticles may also contribute to ferroptosis induction. The intravenous iron preparation ferumoxytol has also shown to increase ROS and thereby induce ferroptosis in patient derived xenografts from primary AML samples with low ferroportin (). Furthermore, nanoparticles using Fenton reactions to improve ferroptosis are under investigation ().
铁蛋白也可以作为蛋白质笼用于传递其他分子,这是由于其三级结构(194)。由于 FTH 可以被 TFRC 结合并吸收(20),这提供了另一种定向靶向的方式。铁蛋白纳米囊携带细胞色素 C 诱导早幼粒细胞 AML 细胞系凋亡(195)。以 Fe 3 O 4 @SiO 2 -细胞色素 C 为纳米粒子形式传递细胞色素 C,增加了细胞系中细胞色素 C 单独的细胞毒效应约两个数量级(196)。将 erastin 和诱导自噬的雷帕霉素与铁蛋白作为纳米药物的组合显示出与单独给药的药物相比对肿瘤生长的抑制增加(197)。此外,使用饱和铁铁蛋白作为纳米粒子的组成部分也可能有助于诱导铁死亡。静脉注射的铁制剂 ferumoxytol 还显示出增加 ROS 并从原发 AML 样本中低铁蛋白的患者来源异种移植物中诱导铁死亡(198)。此外,正在研究使用芬顿反应改善铁死亡的纳米粒子(199)。

Taken together, a couple of possible therapeutic agents have been developed that hijack iron proteins for target delivery. Their effectivity has been demonstrated in vitro and in vivo. Clinical studies have to further evaluate their use in patients.

Perspectives 观点

In this review, we demonstrated the clinical significance of iron homeostasis in MDS and AML patients. Iron metabolism has been shown to impact multiple intracellular functions, the production of ROS, the microenvironment as well as the susceptibility to infections. Markers of iron overload were demonstrated to have prognostic relevance although the impact of an altered iron metabolism on patient outcome in MDS and AML is still under debate as markers of iron overload are highly influenced by inflammatory signals and complicate the detection of causative associations. Supporting a partially causative connection between iron metabolism and patient outcome, therapeutics addressing the iron balance as ICT were found to improve the outcome especially in low/intermediate-1 risk MDS patients. As recurrent red blood cell transfusions constitute the major source of secondary iron overload in MDS and AML patients, a more restrictive application should be considered. Moreover, various agents targeting proteins involved in iron homeostasis or inducing ferroptosis are investigated preclinically or are in early clinical development. With a more detailed understanding of the pathophysiology of MDS and AML in the context of iron, future development of new iron-targeting strategies may lead to better patient outcomes. Therefore, basic research further investigating the processes involved in iron homeostasis linked with redox balance and leukemia is inevitable. Moreover, clinical studies analyzing reliable markers for pathophysiological active iron overload and prospective studies exploring function of iron-homeostasis targeting drugs are essential. Especially the combination of iron-homeostasis targeting drugs with other antileukemic agents constitutes a promising approach due to potential synergistic effects and should therefore be further elucidated.
在这篇综述中,我们展示了铁稳态在 MDS 和 AML 患者中的临床意义。已经显示铁代谢影响多个细胞内功能、ROS 的产生、微环境以及感染易感性。铁超载标志物已被证明具有预后相关性,尽管铁代谢异常对 MDS 和 AML 患者预后的影响仍在争论之中,因为铁超载标志物受炎症信号的影响很大,使得原因相关性的检测变得复杂。支持铁代谢与患者预后之间存在部分因果关系的连接,治疗以调节铁平衡的 ICT 被发现可以改善特别是低/中等-1 风险的 MDS 患者的预后。由于反复输注红细胞构成了 MDS 和 AML 患者继发性铁超载的主要来源,应考虑更为严格的应用。此外,正在临床前研究或早期临床开发中的各种靶向参与铁稳态的蛋白或诱导铁死亡的药物正在研究中。 通过对 MDS 和 AML 在铁元素背景下病理生理学的更详细了解,未来发展新的针对铁元素的策略可能会带来更好的患者预后。因此,进一步开展基础研究,探讨与氧化还原平衡和白血病相关的铁元素稳态过程是不可避免的。此外,分析可靠的标志物以评估病理活性铁元素过载的临床研究和探索铁元素稳态靶向药物功能的前瞻性研究是必不可少的。特别是将铁元素稳态靶向药物与其他抗白血病药物结合使用构成了一种有前景的方法,由于可能产生协同效应,因此应进一步阐明。

Author Contributions 作者贡献

Conceptualization was done by SW, AP, and HS. Investigation and writing of the draft was done by SW and AP. Review and editing of the draft was done by NK, FS, and HS. Supervision was done by HS. All authors contributed to the article and approved the submitted version.
概念化由 SW、AP 和 HS 完成。调查和起草工作由 SW 和 AP 完成。审查和编辑起草工作由 NK、FS 和 HS 完成。监督由 HS 完成。所有作者都为文章做出了贡献并批准了提交的版本。

Funding 资金

This work was supported by the German Cancer Consortium (DKTK) (SW, HS), the Alfred and Angeliga Gutermuth-Stiftung (SW), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—SFB1177 TP E07 (HS) and SFB815 TP A10 (HS, NK) and by the LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research and the Arts [III L 5-519/03/03.001-(0015)].
这项工作得到德国癌症联盟(DKTK)(SW,HS)、阿尔弗雷德和安吉利加·古特穆特基金会(SW)、德国研究基金会(DFG,德国研究基金会)—SFB1177 TP E07(HS)和 SFB815 TP A10(HS,NK)的支持,以及由黑森州高等教育、研究和艺术部(III L 5-519/03/03.001-(0015))资助的 LOEWE 中心法兰克福癌症研究所(FCI)。

Conflict of Interest 利益冲突

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations 缩写

AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; DFS, disease-free survival; GvHD, graft-versus-host disease; HFE, hereditary hemochromatosis protein; HSCT, hematopoietic stem cell transplantation; ICT, iron chelation therapy; IRE, iron-responsive elements; IRP, iron-responsive element binding protein; LCI, labile cellular iron; LPI, labile plasma iron; MDS, myelodysplastic syndrome; NRM, non-relapse mortality; NTBI, non-transferrin-bound iron; OS, overall survival; PFS, progressive-free survival; PUFA, polyunsaturated fatty acid; RFS, relapse-free survival; ROS, reactive oxygen species; TAM, tumor-associated macrophage; TCA, tricarboxylic acid cycle; TFR, transferrin receptor.


1. Porwit A, Saft L. The AML–MDS interface—leukemic transformation in myelodysplastic syndromes. J Hematopathol (2011) 4(2):69–79. 10.1007/s12308-011-0088-6 [CrossRef] []
2. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al.. SEER Cancer Statistics Review (2020). Available at: https://seer.cancer.gov/csr/1975_2017 (Accessed September 9, 2020).
3. Vinchi F, Hell S, Platzbecker U. Controversies on the Consequences of Iron Overload and Chelation in MDS. Hemasphere (2020) 4(3):e357. 10.1097/HS9.0000000000000357 [PMC free article] [PubMed] [CrossRef] []
4. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol (2014) 10(1):9–17. 10.1038/nchembio.1416 [PubMed] [CrossRef] []
5. Greenberg PL. Myelodysplastic syndromes: iron overload consequences and current chelating therapies. J Natl Compr Canc Netw (2006) 4(1):91–6. 10.6004/jnccn.2006.0010 [PubMed] [CrossRef] []
6. Cazzola M, Della Porta MG, Malcovati L. Clinical relevance of anemia and transfusion iron overload in myelodysplastic syndromes. Hematol Am Soc Hematol Educ Program (2008) 2008(1):166–75. 10.1182/asheducation-2008.1.166 [PubMed] [CrossRef] []
7. Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis (1999) 5(3):346–52. 10.3201/eid0503.990305 [PMC free article] [PubMed] [CrossRef] []
8. Lebon D, Vergez F, Bertoli S, Harrivel V, de Botton S, Micol J-B, et al.. Hyperferritinemia at diagnosis predicts relapse and overall survival in younger AML patients with intermediate-risk cytogenetics. Leuk Res (2015) 39(8):818–21. 10.1016/j.leukres.2015.05.001 [PubMed] [CrossRef] []
9. Bertoli S, Paubelle E, Bérard E, Saland E, Thomas X, Tavitian S, et al.. Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia. Eur J Haematol (2019) 102(2):131–42. 10.1111/ejh.13183 [PubMed] [CrossRef] []
10. Gasparetto M, Pei S, Minhajuddin M, Stevens B, Smith CA, Seligman P. Low ferroportin expression in AML is correlated with good risk cytogenetics, improved outcomes and increased sensitivity to chemotherapy. Leuk Res (2019) 80:1–10. 10.1016/j.leukres.2019.02.011 [PubMed] [CrossRef] []
11. Wang F, Lv H, Zhao B, Zhou L, Wang S, Luo J, et al.. Iron and leukemia: new insights for future treatments. J Exp Clin Cancer Res (2019) 38(1):406. 10.1186/s13046-019-1397-3 [PMC free article] [PubMed] [CrossRef] []
12. Andrews NC. Disorders of iron metabolism. N Engl J Med (1999) 341(26):1986–95. 10.1056/NEJM199912233412607 [PubMed] [CrossRef] []
13. Yang J, Moses MA. Lipocalin 2: a multifaceted modulator of human cancer. Cell Cycle (Georgetown Tex) (2009) 8(15):2347–52. 10.4161/cc.8.15.9224 [PMC free article] [PubMed] [CrossRef] []
14. West A-R, Oates P-S. Mechanisms of heme iron absorption: current questions and controversies. World J Gastroenterol (2008) 14(26):4101–10. 10.3748/wjg.14.4101 [PMC free article] [PubMed] [CrossRef] []
15. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet (2014) 46(7):678–84. 10.1038/ng.2996 [PMC free article] [PubMed] [CrossRef] []
16. Tanno T, Bhanu NV, Oneal PA, Goh S-H, Staker P, Lee YT, et al.. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med (2007) 13(9):1096–101. 10.1038/nm1629 [PubMed] [CrossRef] []
17. Tanno T, Porayette P, Sripichai O, Noh S-J, Byrnes C, Bhupatiraju A, et al.. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood (2009) 114(1):181–6. 10.1182/blood-2008-12-195503 [PMC free article] [PubMed] [CrossRef] []
18. Fang Z, Zhu Z, Zhang H, Peng Y, Liu J, Lu H, et al.. GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1-mediated BMP-SMAD signalling suppression. Br J Haematol (2020) 188(2):321–31. 10.1111/bjh.16156 [PMC free article] [PubMed] [CrossRef] []
19. Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med (2012) 366(4):348–59. 10.1056/NEJMra1004967 [PubMed] [CrossRef] []
20. Li L, Fang CJ, Ryan JC, Niemi EC, Lebrón JA, Björkman PJ, et al.. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci U S A (2010) 107(8):3505–10. 10.1073/pnas.0913192107 [PMC free article] [PubMed] [CrossRef] []
21. Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, et al.. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLife (2015) 4:e10308. 10.7554/eLife.10308 [PMC free article] [PubMed] [CrossRef] []
22. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell (2010) 142(1):24–38. 10.1016/j.cell.2010.06.028 [PubMed] [CrossRef] []
23. Taoka K, Kumano K, Nakamura F, Hosoi M, Goyama S, Imai Y, et al.. The effect of iron overload and chelation on erythroid differentiation. Int J Hematol (2012) 95(2):149–59. 10.1007/s12185-011-0988-3 [PubMed] [CrossRef] []
24. Tanaka H, Espinoza JL, Fujiwara R, Rai S, Morita Y, Ashida T, et al.. Excessive reactive iron impairs hematopoiesis by affecting both immature hematopoietic cells and stromal cells. Cells (2019) 8(3):226. 10.3390/cells8030226 [PMC free article] [PubMed] [CrossRef] []
25. Lu W, Zhao M, Rajbhandary S, Xie F, Chai X, Mu J, et al.. Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients. Eur J Haematol (2013) 91(3):249–61. 10.1111/ejh.12159 [PubMed] [CrossRef] []
26. Wilkinson N, Pantopoulos K. The IRP/IRE system in vivo: insights from mouse models. Front Pharmacol (2014) 5:176. 10.3389/fphar.2014.00176 [PMC free article] [PubMed] [CrossRef] []
27. Muto Y, Nishiyama M, Nita A, Moroishi T, Nakayama KI. Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. Nat Commun (2017) 8:16114. 10.1038/ncomms16114 [PMC free article] [PubMed] [CrossRef] []
28. Pfeiffer CM, Looker AC. Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. Am J Clin Nutr (2017) 106(Suppl 6):1606S–14S. 10.3945/ajcn.117.155887 [PMC free article] [PubMed] [CrossRef] []
29. Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood (2003) 102(7):2670–7. 10.1182/blood-2003-03-0807 [PubMed] [CrossRef] []
30. Evans RW, Rafique R, Zarea A, Rapisarda C, Cammack R, Evans PJ, et al.. Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera. J Biol Inorg Chem (2008) 13(1):57–74. 10.1007/s00775-007-0297-8 [PubMed] [CrossRef] []
31. Jensen P-D. Evaluation of iron overload. Br J Haematol (2004) 124(6):697–711. 10.1111/j.1365-2141.2004.04838.x [PubMed] [CrossRef] []
32. Porter JB. Practical management of iron overload. Br J Haematol (2001) 115(2):239–52. 10.1046/j.1365-2141.2001.03195.x [PubMed] [CrossRef] []
33. Cui R, Gale RP, Zhu G, Xu Z, Qin T, Zhang Y, et al.. Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. Leuk Res (2014) 38(5):545–50. 10.1016/j.leukres.2014.01.016 [PMC free article] [PubMed] [CrossRef] []
34. Santini V, Girelli D, Sanna A, Martinelli N, Duca L, Campostrini N, et al.. Hepcidin levels and their determinants in different types of myelodysplastic syndromes. PLoS One (2011) 6(8):e23109. 10.1371/journal.pone.0023109 [PMC free article] [PubMed] [CrossRef] []
35. Winder A, Lefkowitz R, Ghoti H, Leiba M, Ganz T, Nemeth E, et al.. Urinary hepcidin excretion in patients with myelodysplastic syndrome and myelofibrosis. Br J Haematol (2008) 142(4):669–71. 10.1111/j.1365-2141.2008.07225.x [PubMed] [CrossRef] []
36. Bondu S, Alary A-S, Lefèvre C, Houy A, Jung G, Lefebvre T, et al.. A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome. Sci Transl Med (2019) 11(500):eaav5467. 10.1126/scitranslmed.aav5467 [PMC free article] [PubMed] [CrossRef] []
37. Hoeks M, Bagguley T, van Marrewijk C, Smith A, Bowen D, Culligan D, et al.. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome. Leukemia (2020). 10.1038/s41375-020-01022-2 [PMC free article] [PubMed] [CrossRef] []
38. Wermke M, Eckoldt J, Götze KS, Klein SA, Bug G, de Wreede LC, et al.. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial. Lancet Haematol (2018) 5(5):e201–10. 10.1016/S2352-3026(18)30036-X [PubMed] [CrossRef] []
39. Duca L, Cappellini MD, Baronciani D, Pilo F, Targhetta C, Visani G, et al.. Non-transferrin-bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload. Am J Hematol (2018) 93(9):E250–2. 10.1002/ajh.25201 [PubMed] [CrossRef] []
40. Sahlstedt L, Ebeling F, von Bonsdorff L, Parkkinen J, Ruutu T. Non-transferrin-bound iron during allogeneic stem cell transplantation. Br J Haematol (2001) 113(3):836–8. 10.1046/j.1365-2141.2001.02820.x [PubMed] [CrossRef] []
41. Aulbert E, Schmidt CG. Ferritin—a tumor marker in myeloid leukemia. Cancer Detect Prev (1985) 8(1-2):297–302. [PubMed] []
42. Cheng P-P, Sun Z-Z, Jiang F, Tang Y-T, Jiao X-Y. Hepcidin expression in patients with acute leukaemia. Eur J Clin Invest (2012) 42(5):517–25. 10.1111/j.1365-2362.2011.02608.x [PubMed] [CrossRef] []
43. Eisfeld A-K, Westerman M, Krahl R, Leiblein S, Liebert UG, Hehme M, et al.. Highly elevated serum hepcidin in patients with acute myeloid leukemia prior to and after allogeneic hematopoietic cell transplantation: does this protect from excessive parenchymal iron loading? Adv Hematol (2011) 2011:491058. 10.1155/2011/491058 [PMC free article] [PubMed] [CrossRef] []
44. Wang Y, Gao A, Zhao H, Lu P, Cheng H, Dong F, et al.. Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3. Leukemia (2016) 30(9):1897–908. 10.1038/leu.2016.81 [PubMed] [CrossRef] []
45. Pereira A, Nomdedeu M, Aguilar J-L, Belkaid M, Carrió A, Cobo F, et al.. Transfusion intensity, not the cumulative red blood cell transfusion burden, determines the prognosis of patients with myelodysplastic syndrome on chronic transfusion support. Am J Hematol (2011) 86(3):245–50. 10.1002/ajh.21959 [PubMed] [CrossRef] []
46. Harnan S, Ren S, Gomersall T, Everson-Hock ES, Sutton A, Dhanasiri S, et al.. Association between Transfusion Status and Overall Survival in Patients with Myelodysplastic Syndromes: A Systematic Literature Review and Meta-Analysis. Acta Haematol (2016) 136(1):23–42. 10.1159/000445163 [PubMed] [CrossRef] []
47. de Swart L, Crouch S, Hoeks M, Smith A, Langemeijer S, Fenaux P, et al.. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica (2020) 105(3):632–9. 10.3324/haematol.2018.212217 [PMC free article] [PubMed] [CrossRef] []
48. Cannas G, Fattoum J, Raba M, Dolange H, Barday G, François M, et al.. Transfusion dependency at diagnosis and transfusion intensity during initial chemotherapy are associated with poorer outcomes in adult acute myeloid leukemia. Ann Hematol (2015) 94(11):1797–806. 10.1007/s00277-015-2456-2 [PubMed] [CrossRef] []
49. Ihlow J, Gross S, Sick A, Schneider T, Flörcken A, Burmeister T, et al.. high serum ferritin at initial diagnosis has a negative impact on long-term survival. Leuk Lymphoma (2019) 60(1):69–77. 10.1080/10428194.2018.1461860 [PubMed] [CrossRef] []
50. Tachibana T, Andou T, Tanaka M, Ito S, Miyazaki T, Ishii Y, et al.. Clinical significance of serum ferritin at diagnosis in patients with acute myeloid leukemia: a YACHT multicenter retrospective study. Clin Lymphoma Myeloma Leuk (2018) 18(6):415–21. 10.1016/j.clml.2018.03.009 [PubMed] [CrossRef] []
51. Meyer SC, O’Meara A, Buser AS, Tichelli A, Passweg JR, Stern M. Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation. Biol Blood Marrow Transplant (2013) 19(3):440–4. 10.1016/j.bbmt.2012.10.012 [PubMed] [CrossRef] []
52. Yan Z, Chen X, Wang H, Chen Y, Chen L, Wu P, et al.. Effect of pre-transplantation serum ferritin on outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation: a meta-analysis. Med (Baltimore) (2018) 97(27):e10310. 10.1097/MD.0000000000010310 [PMC free article] [PubMed] [CrossRef] []
53. Armand P, Kim HT, Virtanen JM, Parkkola RK, Itälä-Remes MA, Majhail NS, et al.. Iron overload in allogeneic hematopoietic cell transplantation outcome: a meta-analysis. Biol Blood Marrow Transplant (2014) 20(8):1248–51. 10.1016/j.bbmt.2014.04.024 [PMC free article] [PubMed] [CrossRef] []
54. Yeh CJ, Taylor CG, Faulk WP. Transferrin binding by peripheral blood mononuclear cells in human lymphomas, myelomas and leukemias. Vox Sang (1984) 46(4):217–23. 10.1159/000466183 [PubMed] [CrossRef] []
55. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem (2000) 275(22):16618–25. 10.1074/jbc.M908846199 [PubMed] [CrossRef] []
56. West AP, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem (2000) 275(49):38135–8. 10.1074/jbc.C000664200 [PubMed] [CrossRef] []
57. Roetto A, Di Cunto F, Pellegrino RM, Hirsch E, Azzolino O, Bondi A, et al.. Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues. Blood (2010) 115(16):3382–9. 10.1182/blood-2009-09-240960 [PubMed] [CrossRef] []
58. Scott CS, Ramsden W, Limbert HJ, Master PS, Roberts BE. Membrane transferrin receptor (TfR) and nuclear proliferation-associated Ki-67 expression in hemopoietic malignancies. Leukemia (1988) 2(7):438–42. [PubMed] []
59. Liu Q, Wang M, Hu Y, Xing H, Chen X, Zhang Y, et al.. Significance of CD71 expression by flow cytometry in diagnosis of acute leukemia. Leuk Lymphoma (2014) 55(4):892–8. 10.3109/10428194.2013.819100 [PubMed] [CrossRef] []
60. Lyons RM, Marek BJ, Paley C, Esposito J, McNamara K, Richards PD, et al.. Relation between chelation and clinical outcomes in lower-risk patients with myelodysplastic syndromes: Registry analysis at 5 years. Leuk Res (2017) 56:88–95. 10.1016/j.leukres.2017.01.033 [PubMed] [CrossRef] []
61. Lyons VJ, Pappas D. Affinity separation and subsequent terminal differentiation of acute myeloid leukemia cells using the human transferrin receptor (CD71) as a capture target. Analyst (2019) 144(10):3369–80. 10.1039/C8AN02357C [PubMed] [CrossRef] []
62. Kollia P, Stavroyianni N, Stamatopoulos K, Zoi K, Viniou N, Mantzourani M, et al.. Molecular analysis of transferrin receptor mRNA expression in acute myeloid leukaemia. Br J Haematol (2001) 115(1):19–24. 10.1046/j.1365-2141.2001.03065.x [PubMed] [CrossRef] []
63. Wu B, Shi N, Sun L, Liu L. Clinical value of high expression level of CD71 in acute myeloid leukemia. Neoplasma (2016) 63(5):809–15. 10.4149/neo_2016_519 [PubMed] [CrossRef] []
64. Nakamaki T, Kawabata H, Saito B, Matsunawa M, Suzuki J, Adachi D, et al.. Elevated levels of transferrin receptor 2 mRNA, not transferrin receptor 1 mRNA, are associated with increased survival in acute myeloid leukaemia. Br J Haematol (2004) 125(1):42–9. 10.1111/j.1365-2141.2004.04866.x [PubMed] [CrossRef] []
65. Di Savino A, Gaidano V, Palmieri A, Crasto F, Volpengo A, Lorenzatti R, et al.. Clinical significance of TFR2 and EPOR expression in bone marrow cells in myelodysplastic syndromes. Br J Haematol (2017) 176(3):491–5. 10.1111/bjh.13968 [PubMed] [CrossRef] []
66. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood (2001) 98(9):2714–9. 10.1182/blood.V98.9.2714 [PubMed] [CrossRef] []
67. Devireddy LR, Gazin C, Zhu X, Green MR. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell (2005) 123(7):1293–305. 10.1016/j.cell.2005.10.027 [PubMed] [CrossRef] []
68. Liu Z, Ciocea A, Devireddy L. Endogenous siderophore 2,5-dihydroxybenzoic acid deficiency promotes anemia and splenic iron overload in mice. Mol Cell Biol (2014) 34(13):2533–46. 10.1128/MCB.00231-14 [PMC free article] [PubMed] [CrossRef] []
69. Yang W-C, Lin P-M, Yang M-Y, Liu Y-C, Chang C-S, Chou W-C, et al.. Higher lipocalin 2 expression may represent an independent favorable prognostic factor in cytogenetically normal acute myeloid leukemia. Leuk Lymphoma (2013) 54(8):1614–25. 10.3109/10428194.2012.749402 [PubMed] [CrossRef] []
70. Yang W-C, Tsai W-C, Lin P-M, Yang M-Y, Liu Y-C, Chang C-S, et al.. Human BDH2, an anti-apoptosis factor, is a novel poor prognostic factor for de novo cytogenetically normal acute myeloid leukemia. J BioMed Sci (2013) 20:58. 10.1186/1423-0127-20-58 [PMC free article] [PubMed] [CrossRef] []
71. Yang W-C, Lin S-F, Wang S-C, Tsai W-C, Wu C-C, Wu S-C. The effects of human BDH2 on the cell cycle, differentiation, and apoptosis and associations with leukemia transformation in myelodysplastic syndrome. Int J Mol Sci (2020) 21(9):3033. 10.3390/ijms21093033 [PMC free article] [PubMed] [CrossRef] []
72. Moreaux J, Kassambara A, Hose D, Klein B. STEAP1 is overexpressed in cancers: a promising therapeutic target. Biochem Biophys Res Commun (2012) 429(3-4):148–55. 10.1016/j.bbrc.2012.10.123 [PubMed] [CrossRef] []
73. Wang W, Grier DD, Woo J, Ward M, Sui G, Torti SV, et al.. Ferritin H is a novel marker of early erythroid precursors and macrophages. Histopathology (2013) 62(6):931–40. 10.1111/his.12101 [PubMed] [CrossRef] []
74. Zolea F, Biamonte F, Candeloro P, Di Sanzo M, Cozzi A, Di Vito A, et al.. H ferritin silencing induces protein misfolding in K562 cells: A Raman analysis. Free Radic Biol Med (2015) 89:614–23. 10.1016/j.freeradbiomed.2015.07.161 [PubMed] [CrossRef] []
75. Chirillo R, Aversa I, Di Vito A, Salatino A, Battaglia AM, Sacco A, et al.. FtH-Mediated ROS Dysregulation Promotes CXCL12/CXCR4 Axis Activation and EMT-Like Trans-Differentiation in Erythroleukemia K562 Cells. Front Oncol (2020) 10:698. 10.3389/fonc.2020.00698 [PMC free article] [PubMed] [CrossRef] []
76. Biamonte F, Zolea F, Bisognin A, Di Sanzo M, Saccoman C, Scumaci D, et al.. H-ferritin-regulated microRNAs modulate gene expression in K562 cells. PLoS One (2015) 10(3):e0122105. 10.1371/journal.pone.0122105 [PMC free article] [PubMed] [CrossRef] []
77. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact (2006) 160(1):1–40. 10.1016/j.cbi.2005.12.009 [PubMed] [CrossRef] []
78. Andreyev AY, Kushnareva YE, Murphy AN, Starkov AA. Mitochondrial ROS metabolism: 10 years later. Biochem Biokhim (2015) 80(5):517–31. 10.1134/S0006297915050028 [PMC free article] [PubMed] [CrossRef] []
79. Lushchak OV, Piroddi M, Galli F, Lushchak VI. Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species. Redox Rep Commun Free Radical Res (2014) 19(1):8–15. 10.1179/1351000213Y.0000000073 [PMC free article] [PubMed] [CrossRef] []
80. Gonçalves AC, Cortesão E, Oliveiros B, Alves V, Espadana AI, Rito L, et al.. Oxidative stress and mitochondrial dysfunction play a role in myelodysplastic syndrome development, diagnosis, and prognosis: A pilot study. Free Radical Res (2015) 49(9):1081–94. 10.3109/10715762.2015.1035268 [PubMed] [CrossRef] []
81. Hole PS, Darley RL, Tonks A. Do reactive oxygen species play a role in myeloid leukemias? Blood (2011) 117(22):5816–26. 10.1182/blood-2011-01-326025 [PubMed] [CrossRef] []
82. Saigo K, Takenokuchi M, Hiramatsu Y, Tada H, Hishita T, Takata M, et al.. Oxidative stress levels in myelodysplastic syndrome patients: their relationship to serum ferritin and haemoglobin values. J Int Med Res (2011) 39(5):1941–5. 10.1177/147323001103900539 [PubMed] [CrossRef] []
83. de Souza GF, Barbosa MC, Santos T, Carvalho T, de Freitas RM, Martins MRA, et al.. Increased parameters of oxidative stress and its relation to transfusion iron overload in patients with myelodysplastic syndromes. J Clin Pathol (2013) 66(11):996–8. 10.1136/jclinpath-2012-201288 [PubMed] [CrossRef] []
84. Ivars D, Orero MT, Javier K, Díaz-Vico L, García-Giménez JL, Mena S, et al.. Oxidative imbalance in low/intermediate-1-risk myelodysplastic syndrome patients: The influence of iron overload. Clin Biochem (2017) 50(16-17):911–7. 10.1016/j.clinbiochem.2017.05.018 [PubMed] [CrossRef] []
85. Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harbor Perspect Biol (2013) 5(2):a012559. 10.1101/cshperspect.a012559 [PMC free article] [PubMed] [CrossRef] []
86. Łuczaj W, Skrzydlewska E. DNA damage caused by lipid peroxidation products. Cell Mol Biol Lett (2003) 8(2):391–413. [PubMed] []
87. Chung YJ, Robert C, Gough SM, Rassool FV, Aplan PD. Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome. Leuk Res (2014) 38(1):95–102. 10.1016/j.leukres.2013.07.008 [PMC free article] [PubMed] [CrossRef] []
88. Zeidan AM, Giri S, DeVeaux M, Ballas SK, Duong VH. Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes. Ann Hematol (2019) 98(2):339–50. 10.1007/s00277-018-3539-7 [PubMed] [CrossRef] []
89. Gimferrer E, Nomdedeu J, Gich I, Jesús Barceló M, Baiget M. Prevalence of hemochromatosis related HFE gene mutations in patients with acute myeloid leukemia. Leuk Res (1999) 23(6):597–8. 10.1016/S0145-2126(99)00043-0 [PubMed] [CrossRef] []
90. Viola A, Pagano L, Laudati D, D’Elia R, D’Amico MR, Ammirabile M, et al.. HFE gene mutations in patients with acute leukemia. Leuk Lymphoma (2006) 47(11):2331–4. 10.1080/10428190600821898 [PubMed] [CrossRef] []
91. Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T, Medaglia C, et al.. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal (2014) 21(11):1605–19. 10.1089/ars.2014.5941 [PMC free article] [PubMed] [CrossRef] []
92. Pilo F, Angelucci E. A storm in the niche: Iron, oxidative stress and haemopoiesis. Blood Rev (2018) 32(1):29–35. 10.1016/j.blre.2017.08.005 [PubMed] [CrossRef] []
93. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al.. ROS and ROS-mediated cellular signaling. Oxid Med Cell Longevity (2016) 2016:4350965. 10.1155/2016/4350965 [PMC free article] [PubMed] [CrossRef] []
94. Sillar JR, Germon ZP, DeIuliis GN, Dun MD. The role of reactive oxygen species in acute myeloid leukaemia. Int J Mol Sci (2019) 20(23):6003. 10.3390/ijms20236003 [PMC free article] [PubMed] [CrossRef] []
95. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al.. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell (2012) 149(5):1060–72. 10.1016/j.cell.2012.03.042 [PMC free article] [PubMed] [CrossRef] []
96. Ye F, Chai W, Xie M, Yang M, Yu Y, Cao L, et al.. HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRASQ61L cells. Am J Cancer Res (2019) 9(4):730–9. [PMC free article] [PubMed] []
97. Hole PS, Zabkiewicz J, Munje C, Newton Z, Pearn L, White P, et al.. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood (2013) 122(19):3322–30. 10.1182/blood-2013-04-491944 [PubMed] [CrossRef] []
98. Wei J, Xie Q, Liu X, Wan C, Wu W, Fang K, et al.. Identification the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia. Ann Transl Med (2020) 8(11):678. 10.21037/atm-20-3296 [PMC free article] [PubMed] [CrossRef] []
99. Yusuf RZ, Saez B, Sharda A, van Gastel N, Yu VWC, Baryawno N, et al.. Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers. Blood (2020) 136(11):1303–16. 10.1182/blood.2019001808 [PMC free article] [PubMed] [CrossRef] []
100. Karathedath S, Rajamani BM, Musheer Aalam SM, Abraham A, Varatharajan S, Krishnamurthy P, et al.. Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2. PLoS One (2017) 12(5):e0177227. 10.1371/journal.pone.0177227 [PMC free article] [PubMed] [CrossRef] []
101. Ali D, Mohammad DK, Mujahed H, Jonson-Videsäter K, Nore B, Paul C, et al.. Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells. Br J Haematol (2016) 174(1):117–26. 10.1111/bjh.14036 [PubMed] [CrossRef] []
102. Ladikou EE, Sivaloganathan H, Pepper A, Chevassut T. Acute myeloid leukaemia in its niche: the bone marrow microenvironment in acute myeloid leukaemia. Curr Oncol Rep (2020) 22(3):27. 10.1007/s11912-020-0885-0 [PMC free article] [PubMed] [CrossRef] []
103. Tsay J, Yang Z, Ross FP, Cunningham-Rundles S, Lin H, Coleman R, et al.. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood (2010) 116(14):2582–9. 10.1182/blood-2009-12-260083 [PMC free article] [PubMed] [CrossRef] []
104. Borriello A, Caldarelli I, Speranza MC, Scianguetta S, Tramontano A, Bencivenga D, et al.. Iron overload enhances human mesenchymal stromal cell growth and hampers matrix calcification. Biochim Biophys Acta (2016) 1860(6):1211–23. 10.1016/j.bbagen.2016.01.025 [PubMed] [CrossRef] []
105. Zhang Y, Zhai W, Zhao M, Li D, Chai X, Cao X, et al.. Effects of iron overload on the bone marrow microenvironment in mice. PLoS One (2015) 10(3):e0120219. 10.1371/journal.pone.0120219 [PMC free article] [PubMed] [CrossRef] []
106. Zheng Q, Zhao Y, Guo J, Zhao S, Fei C, Xiao C, et al.. Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway. Cell Death Dis (2018) 9(5):515. 10.1038/s41419-018-0552-7 [PMC free article] [PubMed] [CrossRef] []
107. Okabe H, Suzuki T, Uehara E, Ueda M, Nagai T, Ozawa K. The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice. Eur J Haematol (2014) 93(2):118–28. 10.1111/ejh.12309 [PubMed] [CrossRef] []
108. Nybakken G, Gratzinger D. Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression. Leuk Lymphoma (2016) 57(8):1893–902. 10.3109/10428194.2015.1121259 [PubMed] [CrossRef] []
109. Jung M, Weigert A, Mertens C, Rehwald C, Brüne B. Iron handling in tumor-associated macrophages-is there a new role for lipocalin-2? Front Immunol (2017) 8:1171. 10.3389/fimmu.2017.01171 [PMC free article] [PubMed] [CrossRef] []
110. Jin X, He X, Cao X, Xu P, Xing Y, Sui S, et al.. Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice. Haematologica (2018) 103(10):1627–34. 10.3324/haematol.2018.193128 [PMC free article] [PubMed] [CrossRef] []
111. Kir D, Saluja M, Modi S, Venkatachalam A, Schnettler E, Roy S, et al.. Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis. Oncotarget (2016) 7(40):65348–63. 10.18632/oncotarget.11689 [PMC free article] [PubMed] [CrossRef] []
112. Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, et al.. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. Cancer Cell Int (2010) 10:28. 10.1186/1475-2867-10-28 [PMC free article] [PubMed] [CrossRef] []
113. Coffman LG, Parsonage D, D’Agostino R, Torti FM, Torti SV. Regulatory effects of ferritin on angiogenesis. Proc Natl Acad Sci U S A (2009) 106(2):570–5. 10.1073/pnas.0812010106 [PMC free article] [PubMed] [CrossRef] []
114. Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang (2009) 97(3):185–97. 10.1111/j.1423-0410.2009.01207.x [PubMed] [CrossRef] []
115. Weinberg ED. Iron and infection. Microbiol Rev (1978) 42(1):45–66. 10.1128/MMBR.42.1.45-66.1978 [PMC free article] [PubMed] [CrossRef] []
116. Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol (2008) 6(7):541–52. 10.1038/nrmicro1930 [PubMed] [CrossRef] []
117. Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis (2007) 11(6):482–7. 10.1016/j.ijid.2007.04.007 [PubMed] [CrossRef] []
118. Ricerca BM, Di Girolamo A, Rund D. Infections in thalassemia and hemoglobinopathies: focus on therapy-related complications. Mediterr J Hematol Infect Dis (2009) 1(1):e2009028. 10.4084/MJHID.2009.028 [PMC free article] [PubMed] [CrossRef] []
119. Sivgin S, Baldane S, Kaynar L, Kurnaz F, Pala C, Sivgin H, et al.. Pretransplant iron overload may be associated with increased risk of invasive fungal pneumonia (IFP) in patients that underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Transfus Apher Sci (2013) 48(1):103–8. 10.1016/j.transci.2012.08.003 [PubMed] [CrossRef] []
120. Ozyilmaz E, Aydogdu M, Sucak G, Aki SZ, Ozkurt ZN, Yegin ZA, et al.. Risk factors for fungal pulmonary infections in hematopoietic stem cell transplantation recipients: the role of iron overload. Bone Marrow Transplant (2010) 45(10):1528–33. 10.1038/bmt.2009.383 [PubMed] [CrossRef] []
121. Tunçcan OG, Yegin ZA, Ozkurt ZN, Erbaş G, Akı SZ, Senol E, et al.. High ferritin levels are associated with hepatosplenic candidiasis in hematopoietic stem cell transplant candidates. Int J Infect Dis (2010) 14 Suppl 3:e104–7. 10.1016/j.ijid.2009.11.028 [PubMed] [CrossRef] []
122. Maertens J, Demuynck H, Verbeken EK, Zachée P, Verhoef GE, Vandenberghe P, et al.. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant (1999) 24(3):307–12. 10.1038/sj.bmt.1701885 [PubMed] [CrossRef] []
123. Kanda J, Mizumoto C, Kawabata H, Ichinohe T, Tsuchida H, Tomosugi N, et al.. Clinical significance of serum hepcidin levels on early infectious complications in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant (2009) 15(8):956–62. 10.1016/j.bbmt.2009.04.008 [PubMed] [CrossRef] []
124. Pullarkat V, Sehgal A, Li L, Meng Z, Lin A, Forman S, et al.. Deferasirox exposure induces reactive oxygen species and reduces growth and viability of myelodysplastic hematopoietic progenitors. Leuk Res (2012) 36(8):966–73. 10.1016/j.leukres.2012.03.018 [PubMed] [CrossRef] []
125. Chen J, Lu W-Y, Zhao M-F, Cao X-L, Jiang Y-Y, Jin X, et al.. Reactive oxygen species mediated T lymphocyte abnormalities in an iron-overloaded mouse model and iron-overloaded patients with myelodysplastic syndromes. Ann Hematol (2017) 96(7):1085–95. 10.1007/s00277-017-2985-y [PubMed] [CrossRef] []
126. Furukawa T, Naitoh Y, Kohno H, Tokunaga R, Taketani S. Iron deprivation decreases ribonucleotide reductase activity and DNA synthesis. Life Sci (1992) 50(26):2059–65. 10.1016/0024-3205(92)90572-7 [PubMed] [CrossRef] []
127. Cooper CE, Lynagh GR, Hoyes KP, Hider RC, Cammack R, Porter JB. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem (1996) 271(34):20291–9. 10.1074/jbc.271.34.20291 [PubMed] [CrossRef] []
128. Shapira S, Raanani P, Samara A, Nagler A, Lubin I, Arber N, et al.. Deferasirox selectively induces cell death in the clinically relevant population of leukemic CD34+CD38- cells through iron chelation, induction of ROS, and inhibition of HIF1α expression. Exp Hematol (2019) 70:55–69.e4. 10.1016/j.exphem.2018.10.010 [PubMed] [CrossRef] []
129. Morel I, Cillard J, Lescoat G, Sergent O, Pasdeloup N, Ocaktan AZ, et al.. Antioxidant and free radical scavenging activities of the iron chelators pyoverdin and hydroxypyrid-4-ones in iron-loaded hepatocyte cultures: Comparison of their mechanism of protection with that of desferrioxamine. Free Radical Biol Med (1992) 13(5):499–508. 10.1016/0891-5849(92)90144-6 [PubMed] [CrossRef] []
130. Chaston TB, Watts RN, Yuan J, Des Richardson R. Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves fenton-derived free radical generation. Clin Cancer Res (2004) 10(21):7365–74. 10.1158/1078-0432.CCR-04-0865 [PubMed] [CrossRef] []
131. Gharagozloo M, Khoshdel Z, Amirghofran Z. The effect of an iron (III) chelator, silybin, on the proliferation and cell cycle of Jurkat cells: a comparison with desferrioxamine. Eur J Pharmacol (2008) 589(1-3):1–7. 10.1016/j.ejphar.2008.03.059 [PubMed] [CrossRef] []
132. Tataranni T, Agriesti F, Mazzoccoli C, Ruggieri V, Scrima R, Laurenzana I, et al.. The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells. Br J Haematol (2015) 170(2):236–46. 10.1111/bjh.13381 [PubMed] [CrossRef] []
133. Callens C, Coulon S, Naudin J, Radford-Weiss I, Boissel N, Raffoux E, et al.. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med (2010) 207(4):731–50. 10.1084/jem.20091488 [PMC free article] [PubMed] [CrossRef] []
134. Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz EA. Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica (2010) 95(8):1433–4. 10.3324/haematol.2010.024992 [PMC free article] [PubMed] [CrossRef] []
135. Saigo K, Kono M, Takagi Y, Takenokuchi M, Hiramatsu Y, Tada H, et al.. Deferasirox reduces oxidative stress in patients with transfusion dependency. J Clin Med Res (2013) 5(1):57–60. 10.4021/jocmr1180w [PMC free article] [PubMed] [CrossRef] []
136. Leardi A, Caraglia M, Selleri C, Pepe S, Pizzi C, Notaro R, et al.. Desferioxamine increases iron depletion and apoptosis induced by ara-C of human myeloid leukaemic cells. Br J Haematol (1998) 102(3):746–52. 10.1046/j.1365-2141.1998.00834.x [PubMed] [CrossRef] []
137. Li N, Chen Q, Gu J, Li S, Zhao G, Wang W, et al.. Synergistic inhibitory effects of deferasirox in combination with decitabine on leukemia cell lines SKM-1, THP-1, and K-562. Oncotarget (2017) 8(22):36517–30. 10.18632/oncotarget.16583 [PMC free article] [PubMed] [CrossRef] []
138. Yalcintepe L, Halis E. Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin. Bosn J Basic Med Sci (2016) 16(1):14–20. 10.17305/bjbms.2016.576 [PMC free article] [PubMed] [CrossRef] []
139. Ohyashiki JH, Kobayashi C, Hamamura R, Okabe S, Tauchi T, Ohyashiki K. The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. Cancer Sci (2009) 100(5):970–7. 10.1111/j.1349-7006.2009.01131.x [PubMed] [CrossRef] []
140. Yu R, Wang D, Ren X, Zeng L, Liu Y. The growth-inhibitory and apoptosis-inducing effect of deferoxamine combined with arsenic trioxide on HL-60 xenografts in nude mice. Leuk Res (2014) 38(9):1085–90. 10.1016/j.leukres.2014.05.005 [PubMed] [CrossRef] []
141. Gattermann N, Finelli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A, et al.. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica (2012) 97(9):1364–71. 10.3324/haematol.2011.048546 [PMC free article] [PubMed] [CrossRef] []
142. Gattermann N. Iron overload in myelodysplastic syndromes (MDS). Int J Hematol (2018) 107(1):55–63. 10.1007/s12185-017-2367-1 [PubMed] [CrossRef] []
143. List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, et al.. Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin Oncol (2012) 30(17):2134–9. 10.1200/JCO.2010.34.1222 [PubMed] [CrossRef] []
144. Nolte F, Höchsmann B, Giagounidis A, Lübbert M, Platzbecker U, Haase D, et al.. Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload. Ann Hematol (2013) 92(2):191–8. 10.1007/s00277-012-1594-z [PubMed] [CrossRef] []
145. Angelucci E, Santini V, Di Tucci AA, Quaresmini G, Finelli C, Volpe A, et al.. Deferasirox for transfusion-dependent patients with myelodysplastic syndromes: safety, efficacy, and beyond (GIMEMA MDS0306 Trial). Eur J Haematol (2014) 92(6):527–36. 10.1111/ejh.12300 [PubMed] [CrossRef] []
146. Wong SA, Leitch HA. Iron chelation therapy in lower IPSS risk myelodysplastic syndromes; which subtypes benefit? Leuk Res (2018) 64:24–9. 10.1016/j.leukres.2017.11.005 [PubMed] [CrossRef] []
147. Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al.. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies). Leuk Res (2010) 34(7):864–70. 10.1016/j.leukres.2009.12.004 [PubMed] [CrossRef] []
148. Delforge M, Selleslag D, Beguin Y, Triffet A, Mineur P, Theunissen K, et al.. Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk Res (2014) 38(5):557–63. 10.1016/j.leukres.2014.02.003 [PubMed] [CrossRef] []
149. Cermak J, Jonasova A, Vondrakova J, Walterova L, Hochova I, Siskova M, et al.. Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome. Hemoglobin (2011) 35(3):217–27. 10.3109/03630269.2011.578515 [PubMed] [CrossRef] []
150. Cermak J, Jonasova A, Vondrakova J, Cervinek L, Belohlavkova P, Neuwirtova R. A comparative study of deferasirox and deferiprone in the treatment of iron overload in patients with myelodysplastic syndromes. Leuk Res (2013) 37(12):1612–5. 10.1016/j.leukres.2013.07.021 [PubMed] [CrossRef] []
151. Langemeijer S, de Swart L, Yu G, Smith A, Crouch S, Johnston T, et al.. Impact oftreatment with iron chelators in lower-risk MDS patients participating in the European Leukemianet MDS (EUMDS) registry. Blood (2016) 128(22):3186. 10.1182/blood.V128.22.3186.3186 [CrossRef] []
152. Dou H, Qin Y, Chen G, Zhao Y. Effectiveness and Safety of Deferasirox in Thalassemia with Iron Overload: A Meta-Analysis. Acta Haematol (2019) 141(1):32–42. 10.1159/000494487 [PubMed] [CrossRef] []
153. Hoeks M, Yu G, Langemeijer S, Crouch S, de Swart L, Fenaux P, et al.. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica (2020) 105(3):640–51. 10.3324/haematol.2018.212332 [PMC free article] [PubMed] [CrossRef] []
154. Angelucci E, Li J, Greenberg P, Wu D, Hou M, Montano Figueroa EH, et al.. Iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: a randomized trial. Ann Intern Med (2020) 172(8):513–22. 10.7326/M19-0916 [PubMed] [CrossRef] []
155. Visani G, Guiducci B, Giardini C, Loscocco F, Ricciardi T, Isidori A. Deferasirox improves hematopoiesis after allogeneic hematopoietic SCT. Bone Marrow Transplant (2014) 49(4):585–7. 10.1038/bmt.2013.213 [PubMed] [CrossRef] []
156. Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, et al.. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol (2015) 2(4):e1054549. 10.1080/23723556.2015.1054549 [PMC free article] [PubMed] [CrossRef] []
157. Zeidner JF, Karp JE, Blackford AL, Smith BD, Gojo I, Gore SD, et al.. A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms. Haematologica (2014) 99(4):672–8. 10.3324/haematol.2013.097246 [PMC free article] [PubMed] [CrossRef] []
158. Chaston TB, Lovejoy DB, Watts RN, Des Richardson R. Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin Cancer Res (2003) 9(1):402–14. [PubMed] []
159. Minden MD, Hogge DE, Weir SJ, Kasper J, Webster DA, Patton L, et al.. Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol (2014) 89(4):363–8. 10.1002/ajh.23640 [PubMed] [CrossRef] []
160. Vlachodimitropoulou E, Chen Y-L, Garbowski M, Koonyosying P, Psaila B, Sola-Visner M, et al.. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood (2017) 130(17):1923–33. 10.1182/blood-2016-10-740241 [PMC free article] [PubMed] [CrossRef] []
161. Kao Y-R, Chen J, Narayanagari S-R, Todorova TI, Aivalioti MM, Ferreira M, et al.. Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag. Sci Transl Med (2018) 10(458):eaas9563. 10.1126/scitranslmed.aas9563 [PMC free article] [PubMed] [CrossRef] []
162. Platzbecker U, Wong RSM, Verma A, Abboud C, Araujo S, Chiou T-J, et al.. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase ½ trial. Lancet Haematol (2015) 2(10):e417–26. 10.1016/S2352-3026(15)00149-0 [PubMed] [CrossRef] []
163. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, et al.. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol (2018) 5(1):e34–43. 10.1016/S2352-3026(17)30228-4 [PubMed] [CrossRef] []
164. Frey N, Jang JH, Szer J, Illés Á, Kim H-J, Ram R, et al.. Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study. Lancet Haematol (2019) 6(3):e122–31. 10.1016/S2352-3026(18)30231-X [PubMed] [CrossRef] []
165. Taetle R, Honeysett JM, Trowbridge I. Effects of anti-transferrin receptor antibodies on growth of normal and malignant myeloid cells. Int J Cancer (1983) 32(3):343–9. 10.1002/ijc.2910320314 [PubMed] [CrossRef] []
166. Callens C, Moura IC, Lepelletier Y, Coulon S, Renand A, Dussiot M, et al.. Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody. Leukemia (2008) 22(1):42–8. 10.1038/sj.leu.2404958 [PubMed] [CrossRef] []
167. Crépin R, Goenaga A-L, Jullienne B, Bougherara H, Legay C, Benihoud K, et al.. Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. Cancer Res (2010) 70(13):5497–506. 10.1158/0008-5472.CAN-10-0938 [PubMed] [CrossRef] []
168. Neiveyans M, Melhem R, Arnoult C, Bourquard T, Jarlier M, Busson M, et al.. A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions. mAbs (2019) 11(3):593–605. 10.1080/19420862.2018.1564510 [PMC free article] [PubMed] [CrossRef] []
169. White S, Taetle R, Seligman PA, Rutherford M, Trowbridge IS. Combinations of anti-transferrin receptor monoclonal antibodies inhibit human tumor cell growth in vitro and in vivo: evidence for synergistic antiproliferative effects. Cancer Res (1990) 50(19):6295–301. [PubMed] []
170. Brooks D, Taylor C, Dos Santos B, Linden H, Houghton A, Hecht TT, et al.. Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6. Clin Cancer Res (1995) 1(11):1259–65. [PubMed] []
171. Nicholls A, Lickliter J, Tozzi L, Liu D, Shames R. Hepcidin mimetic ptg-300 induces dose-related and sustained reductions in serum iron and transferrin saturation in healthy subjects. In: EHA Library (https://library.ehaweb.org/) of the 23rd EHA Congress (2018). Abstract S895. []
172. Lal A, Piga A, Viprakasit V, Maynard J, Kattamis A, Yaeger D, et al.. A phase 1, open-label study to determine the safety, tolerability, and pharmacokinetics of escalating doses of LJPC-401 (synthetic human hepcidin) in patients with iron overload. In: EHA Library (https://library.ehaweb.org/) of the 23rd EHA Congress (2018). Abstract S894. []
173. Crielaard BJ, Lammers T, Rivella S. Targeting iron metabolism in drug discovery and delivery. Nat Rev Drug Discov (2017) 16(6):400–23. 10.1038/nrd.2016.248 [PMC free article] [PubMed] [CrossRef] []
174. Zhao N, Nizzi CP, Anderson SA, Wang J, Ueno A, Tsukamoto H, et al.. Low intracellular iron increases the stability of matriptase-2. J Biol Chem (2015) 290(7):4432–46. 10.1074/jbc.M114.611913 [PMC free article] [PubMed] [CrossRef] []
175. Schmidt PJ, Toudjarska I, Sendamarai AK, Racie T, Milstein S, Bettencourt BR, et al.. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood (2013) 121(7):1200–8. 10.1182/blood-2012-09-453977 [PMC free article] [PubMed] [CrossRef] []
176. Beckmann A-M, Maurer E, Lülsdorff V, Wilms A, Furtmann N, Bajorath J, et al.. En route to new therapeutic options for iron overload diseases: matriptase-2 as a target for Kunitz-type inhibitors. Chembiochem (2016) 17(7):595–604. 10.1002/cbic.201500651 [PubMed] [CrossRef] []
177. Sheetz M, Barrington P, Callies S, Berg PH, McColm J, Marbury T, et al.. Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease. Br J Clin Pharmacol (2019) 85(5):935–48. 10.1111/bcp.13877 [PMC free article] [PubMed] [CrossRef] []
178. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al.. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell (2017) 171(2):273–85. 10.1016/j.cell.2017.09.021 [PMC free article] [PubMed] [CrossRef] []
179. Zhao Y, Li Y, Zhang R, Wang F, Wang T, Jiao Y. The role of Erastin in ferroptosis and its prospects in cancer therapy. OncoTargets Ther (2020) 13:5429–41. 10.2147/OTT.S254995 [PMC free article] [PubMed] [CrossRef] []
180. Wu Z, Geng Y, Lu X, Shi Y, Wu G, Zhang M, et al.. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A (2019) 116(8):2996–3005. 10.1073/pnas.1819728116 [PMC free article] [PubMed] [CrossRef] []
181. Battipaglia G, Massoud R, Ahmed SO, Legrand O, El Cheikh J, Youniss R, et al.. Efficacy and Feasibility of Sorafenib as a Maintenance Agent After Allogeneic Hematopoietic Stem Cell Transplantation for Fms-like Tyrosine Kinase 3 Mutated Acute Myeloid Leukemia: An Update. Clin Lymphoma Myeloma Leuk (2019) 19(8):506–8. 10.1016/j.clml.2019.04.004 [PubMed] [CrossRef] []
182. Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, et al.. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre Sormain trial. Blood (2018) 132(Supplement 1):661. Abstract retrieved from 60th ASH Annual Meeting 2018. 10.1182/blood-2018-99-112614 [CrossRef] []
183. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al.. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife (2014) 3:e02523. 10.7554/eLife.02523 [PMC free article] [PubMed] [CrossRef] []
184. Du J, Wang T, Li Y, Zhou Y, Wang X, Yu X, et al.. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med (2019) 131:356–69. 10.1016/j.freeradbiomed.2018.12.011 [PubMed] [CrossRef] []
185. Lv Q, Niu H, Yue L, Liu J, Yang L, Liu C, et al.. Abnormal Ferroptosis in Myelodysplastic Syndrome. Front Oncol (2020) 10:1656. 10.3389/fonc.2020.01656 [PMC free article] [PubMed] [CrossRef] []
186. Oh S, Kim BJ, Singh NP, Lai H, Sasaki T. Synthesis and anti-cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett (2009) 274(1):33–9. 10.1016/j.canlet.2008.08.031 [PubMed] [CrossRef] []
187. Yang X, Koh CG, Liu S, Pan X, Santhanam R, Yu B, et al.. Transferrin receptor-targeted lipid nanoparticles for delivery of an antisense oligodeoxyribonucleotide against Bcl-2. Mol Pharma (2009) 6(1):221–30. 10.1021/mp800149s [PMC free article] [PubMed] [CrossRef] []
188. Yuan Y, Zhang L, Cao H, Yang Y, Zheng Y, Yang X-j. A polyethylenimine-containing and transferrin-conjugated lipid nanoparticle system for antisense oligonucleotide delivery to AML. BioMed Res Int (2016) 2016:1287128. 10.1155/2016/1287128 [PMC free article] [PubMed] [CrossRef] []
189. Dorrance AM, Neviani P, Ferenchak GJ, Huang X, Nicolet D, Maharry KS, et al.. Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Leukemia (2015) 29(11):2143–53. 10.1038/leu.2015.139 [PMC free article] [PubMed] [CrossRef] []
190. Zhu B, Zhang H, Yu L. Novel transferrin modified and doxorubicin loaded Pluronic 85/lipid-polymeric nanoparticles for the treatment of leukemia: In vitro and in vivo therapeutic effect evaluation. Biomed Pharmacother = Biomed Pharmacother (2017) 86:547–54. 10.1016/j.biopha.2016.11.121 [PubMed] [CrossRef] []
191. Fang Z, Sun Y, Cai C, Fan R, Guo R, Xie D. Targeted delivery of DOX by transferrin conjugated DSPE-PEG nanoparticles in leukemia therapy. Int J Polym Mat Polym Biomater (2019) 7:1–10. 10.1080/00914037.2019.1685516 [CrossRef] []
192. Sun Y, Sun Z-L. Transferrin-conjugated polymeric nanomedicine to enhance the anticancer efficacy of edelfosine in acute myeloid leukemia. Biomed Pharmacother = Biomed Pharmacother (2016) 83:51–7. 10.1016/j.biopha.2016.05.046 [PubMed] [CrossRef] []
193. Khajavinia A, Varshosaz J, Dehkordi AJ. Targeting etoposide to acute myelogenous leukaemia cells using nanostructured lipid carriers coated with transferrin. Nanotechnology (2012) 23(40):405101. 10.1088/0957-4484/23/40/405101 [PubMed] [CrossRef] []
194. Jutz G, van Rijn P, Santos Miranda B, Böker A. Ferritin: a versatile building block for bionanotechnology. Chem Rev (2015) 115(4):1653–701. 10.1021/cr400011b [PubMed] [CrossRef] []
195. Macone A, Masciarelli S, Palombarini F, Quaglio D, Boffi A, Trabuco MC, et al.. Ferritin nanovehicle for targeted delivery of cytochrome C to cancer cells. Sci Rep (2019) 9(1):11749. 10.1038/s41598-019-48037-z [PMC free article] [PubMed] [CrossRef] []
196. Shahabadi N, Falsafi M, Mansouri K. Improving antiproliferative effect of the anticancer drug cytarabine on human promyelocytic leukemia cells by coating on Fe3O4@SiO2 nanoparticles. Colloids Surf B Biointerfaces (2016) 141:213–22. 10.1016/j.colsurfb.2016.01.054 [PubMed] [CrossRef] []
197. Li Y, Wang X, Yan J, Liu Y, Yang R, Pan D, et al.. Nanoparticle ferritin-bound erastin and rapamycin: a nanodrug combining autophagy and ferroptosis for anticancer therapy. Biomater Sci (2019) 7(9):3779–87. 10.1039/C9BM00653B [PubMed] [CrossRef] []
198. Trujillo-Alonso V, Pratt EC, Zong H, Lara-Martinez A, Kaittanis C, Rabie MO, et al.. FDA-approved ferumoxytol displays anti-leukaemia efficacy against cells with low ferroportin levels. Nat Nanotechnol (2019) 14(6):616–22. 10.1038/s41565-019-0406-1 [PMC free article] [PubMed] [CrossRef] []
199. Ranji-Burachaloo H, Gurr PA, Dunstan DE, Qiao GG. Cancer treatment through nanoparticle-facilitated Fenton reaction. ACS Nano (2018) 12(12):11819–37. 10.1021/acsnano.8b07635 [PubMed] [CrossRef] []

Articles from Frontiers in Immunology are provided here courtesy of Frontiers Media SA