Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice

被引:0
|
作者
An, Wenbin [1 ,2 ]
Feola, Maria [1 ]
Levy, Maayan [1 ]
Aluri, Srinivas [3 ]
Ruiz-Martinez, Marc [1 ]
Sridharan, Ashwin [3 ]
Fibach, Eitan [4 ]
Zhu, Xiaofan [2 ]
Verma, Amit [3 ]
Ginzburg, Yelena [1 ]
机构
[1] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA
[2] Chinese Acad Med Sci & Peking Union Med Coll, Inst Hematol & Blood Dis Hosp, State Key Lab Expt Hematol,Nat Clin Res Ctr Blood, Div Pediat Blood Dis Ctr, Tianjin, Peoples R China
[3] Albert Einstein Coll Med, Div Hematol & Med Oncol, Bronx, NY USA
[4] Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Hematol, Jerusalem, Israel
来源
ELIFE | 2023年 / 12卷
关键词
myelodysplastic dyndrome; deferiprone; ineffective erythropoiesis; iron trafficking; Mouse; TERMINAL ERYTHROID-DIFFERENTIATION; PROGNOSTIC SCORING SYSTEM; TRANSFERRIN RECEPTOR 2; MOUSE MODEL; HEPCIDIN SUPPRESSION; MICROCYTIC ANEMIA; MESSENGER-RNA; UNITED-STATES; IN-VIVO; EXPRESSION;
D O I
10.7554/eLife.83103
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Ncoa4 and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.
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页数:26
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