The Role of Iron in Benign and Malignant Hematopoiesis

Abstract

Significance: Iron is an essential element required for sustaining a normal healthy life. However, an excess amount of iron in the bloodstream and tissue generates toxic hydroxyl radicals through Fenton reactions. Henceforth, a balance in iron concentration is extremely important to maintain cellular homeostasis in both normal hematopoiesis and erythropoiesis. Iron deficiency or iron overload can impact hematopoiesis and is associated with many hematological diseases. Recent Advances: The mechanisms of action of key iron regulators such as erythroferrone and the discovery of new drugs, such as ACE-536/luspatercept, are of potential interest to treat hematological disorders, such as b-thalassemia. New therapies targeting inflammation-induced ineffective erythropoiesis are also in progress. Furthermore, emerging evidences support differential interactions between iron and its cellular antioxidant responses of hematopoietic and neighboring stromal cells. Both iron and its systemic regulator, such as hepcidin, play a significant role in regulating erythropoiesis. Critical Issues: Significant pre-clinical studies are on the way and new drugs targeting iron metabolism have been recently approved or are undergoing clinical trials to treat pathological conditions with impaired erythropoiesis such as myelodysplastic syndromes or b-thalassemia. Future Directions: Future studies should explore how iron regulates hematopoiesis in both benign and malignant conditions. Antioxid. Redox Signal. 00, 000-000.

The efficiency and safety evaluation of hemoglobin hydrolysate as a non-heme iron fortifier

“…The increase of DMT1 content indicated that hemoglobin hydrolysate promoted more free Fe 2+ to get into the liver. In general, free Fe 2+ produces hydroxyl free radicals by Fenton reaction, and induces body impairment through oxidative stress [41]. When free Fe 2+ is highly accumulated in liver, CP that catalyzes the transformation of Fe 2+ into Fe 3+ , and PCBP1 and ferritin that transport and store free iron will be released to protect liver from oxidative stress [42,43].…”

The Relationship Between Ferroptosis and Diseases

“…Decreased iron content will lead to iron-deficiency disease. 36 Contrarily, overload of iron content will generate free radicals through the Fenton reaction, resulting in oxidative stress in cells, which eventually leads to cell death. 37 Iron comes primarily from dietary iron and can also be recovered from the body’s liver and aging red blood cells (RBCs).…”

Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine

“…It is interesting to note that patients suffering from hereditary hemochromatosis do not have significantly altered haematopoiesis, despite being subjected to chronic iron overloading [43]. An inherent protection rendered to HSCs within their bone marrow niche, which may not be fully replicated in an in vitro scenario may be responsible for this phenomenon [44]. A multitude of proteins involved in iron homeostasis play an important role in regulating intracellular iron levels.…”

“…Deficiency of one such protein, the F-box and leucine-rich repeat protein 5 (FBXL5) in HSCs causes iron overloading and results in reduced cell numbers, impaired self-renewal and stem cell exhaustion. HSCs from patients suffering from MDS have reduced expression of FBXL5 which may contribute to disease pathology [44]. Thus, iron overloading seems to adversely affect HSC biology and has several pathological consequences.…”