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Iron Metabolism
Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice
Ferrata Storti Foundation
Xin Jin,1* Xiaoyuan He,1* Xiaoli Cao,2 Ping Xu,3 Yi Xing,2 Songnan Sui,3 Luqiao Wang,3 Juanxia Meng,3 Wenyi Lu,3 Rui Cui,3 Hongyan Ni4** and Mingfeng Zhao3,1**
1Nankai University School of Medicine, Tianjin; 2Tianjin Children's Hospital; 3Department of Hematology, Tianjin First Central Hospital and 4Department of Radiology, Tianjin First Central Hospital, Tianjin, PR China
Haematologica 2018 Volume 103(10):1627-1634
*XJ and XYH, and **HYN and MFZ contributed equally to this work.
ABSTRACT
There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the RUNX1S291fs-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injec- tion of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, short- ening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.
Introduction
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid malig- nancy characterized by dysplastic changes in one or more cell lineages, ineffective hematopoiesis, and high risk of leukemic transformation.1,2 Because of chronic ane- mia, up to 80% of MDS patients become transfusion dependent.3 Due to repeated blood transfusion and ineffective hematopoiesis, most MDS patients can eventual- ly develop iron overload. Excessive iron can deposit in the liver, heart, spleen, pan- creas, bone marrow (BM) and other tissues, resulting in tissue damage and fibrosis, and a series of complications which seriously affect the prognosis of MDS patients.4-6 Therefore, iron overload in MDS patients has received great attention from clinicians. Here the question is whether and how iron overload impacts the hematopoietic system in MDS. Indeed, iron-chelation therapy often improves the prognosis of MDS patients, implicating that iron overload has a suppressive effect on hematopoiesis in these subjects. However, how iron overload influences hematopoiesis in MDS still has to be addressed.
RUNX1 (also known as AML1/CBFA2), one of the most common mutation genes in MDS patients, has an important role in hematopoiesis. RUNX1-S291fs is one type of RUNX1 mutation. Previous studies have proved that RUNX1-S291fs mutant can be used to construct an MDS mouse model.7,8 In order to investigate how iron overload affects hematopoiesis in MDS, we generated a RUNX1-S291fs- induced MDS mouse model and subsequently administered iron dextran by intraperitoneal injection to establish an iron overload model in MDS mice.
In this study, we found that iron overload impairs the frequency and function of
Correspondence:
mingfengzhao@sina.com
Received: March 10, 2018. Accepted: June 7, 2018. Pre-published: June 14, 2018.
doi:10.3324/haematol.2018.193128
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1627
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