Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83103 |
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| author | Wenbin An Maria Feola Maayan Levy Srinivas Aluri Marc Ruiz-Martinez Ashwin Sridharan Eitan Fibach Xiaofan Zhu Amit Verma Yelena Ginzburg |
| author_facet | Wenbin An Maria Feola Maayan Levy Srinivas Aluri Marc Ruiz-Martinez Ashwin Sridharan Eitan Fibach Xiaofan Zhu Amit Verma Yelena Ginzburg |
| author_sort | Wenbin An |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T18:54:20Z |
| format | Article |
| id | doaj.art-cedb8c13ba2d4398bcc5cae9fdd1bb2a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T18:54:20Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-cedb8c13ba2d4398bcc5cae9fdd1bb2a2023-12-28T15:35:24ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.83103Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome miceWenbin An0Maria Feola1Maayan Levy2Srinivas Aluri3Marc Ruiz-Martinez4Ashwin Sridharan5Eitan Fibach6Xiaofan Zhu7Amit Verma8https://orcid.org/0000-0002-5408-1673Yelena Ginzburg9https://orcid.org/0000-0002-3496-3783Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Division of Pediatric Blood Diseases Center, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaDivision of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United StatesDivision of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United StatesDivision of Hematology and Medical Oncology, Albert Einstein College of Medicine, Bronx, United StatesDivision of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United StatesDivision of Hematology and Medical Oncology, Albert Einstein College of Medicine, Bronx, United StatesDepartment of Hematology, Hadassah Medical Center, Hebrew University, Jerusalem, IsraelState Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Division of Pediatric Blood Diseases Center, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaDivision of Hematology and Medical Oncology, Albert Einstein College of Medicine, Bronx, United StatesDivision of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United StatesMyelodysplastic 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.https://elifesciences.org/articles/83103myelodysplastic dyndromedeferiproneineffective erythropoiesisiron trafficking |
| spellingShingle | Wenbin An Maria Feola Maayan Levy Srinivas Aluri Marc Ruiz-Martinez Ashwin Sridharan Eitan Fibach Xiaofan Zhu Amit Verma Yelena Ginzburg Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice eLife myelodysplastic dyndrome deferiprone ineffective erythropoiesis iron trafficking |
| title | Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| title_full | Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| title_fullStr | Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| title_full_unstemmed | Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| title_short | Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| title_sort | iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice |
| topic | myelodysplastic dyndrome deferiprone ineffective erythropoiesis iron trafficking |
| url | https://elifesciences.org/articles/83103 |
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