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

Abstract

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.

Construction and Validation of a Novel Ferroptosis-Related Prognostic Model for Acute Myeloid Leukemia

“…Recently, a large number of studies have highlighted the place of targeted ferroptosis in the treatment of AML. Current approaches to treat AML by modulating iron metabolism can be broadly classified into four categories: iron chelators, modulation of proteins involved in iron metabolism, induction of ferroptosis, and delivery of anti-leukemic drugs by ferritin ( Weber et al, 2020 ). Iron chelators prevent the induction of ferroptosis, and deferoxamine (DFO) exerts anti-leukemic effects by blocking ROS elaboration and iron-dependent enzymes.…”

From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox

“…These pathological iron load mechanisms are active regardless of the need for transfusions, although transfusion support considerably worsens this pre-existing overload (9,(13)(14)(15). Indeed, each unit of packed red cells contains 200-250 mg of iron (approximately 100 times the normal daily intake).…”

EnvIRONmental Aspects in Myelodysplastic Syndrome

“…This form of regulated cell death is morphologically, biochemically and genetically distinct from other forms of cell death (e.g., apoptosis, pyroptosis, necroptosis and autophagy) and is triggered by iron-dependent accumulation of lipid peroxides [ 154 , 155 ]. While ferroptosis induction is associated with antileukemic activity in AML cell lines [ 43 , 156 , 157 ], data on MDS are currently limited. According to one recently published study, the cytosine analog used for MDS treatment, decitabine, exerts its antileukemic effect via the generation of ROS.…”

“…In the last decade, the understanding that iron overload is not just a bystander due to multiple RBC transfusions but also has multiple implications for the disease has steadily increased. Many reviews exist on the clinical outcome and implication of iron overload in MDS, on which we will only touch superficially in this review [ 2 , 43 , 44 ]. Herein we particularly focus on molecular aspects related to iron metabolism in MDS and discuss relevant, partly yet unanswered questions related to iron overload and MDS.…”