Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells
Abstract Background Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS tr...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-10-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.610 |
| _version_ | 1811338846164484096 |
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| author | Huafeng Wang Jie Sun Bin Zhang Dandan Zhao Hongyan Tong Herman Wu Xia Li Yingwan Luo Dan Dong Yiyi Yao Tinisha McDonald Anthony S. Stein Monzr M. Al Malki Flavia Pichiorri Nadia Carlesso Ya‐Huei Kuo Guido Marcucci Ling Li Jie Jin |
| author_facet | Huafeng Wang Jie Sun Bin Zhang Dandan Zhao Hongyan Tong Herman Wu Xia Li Yingwan Luo Dan Dong Yiyi Yao Tinisha McDonald Anthony S. Stein Monzr M. Al Malki Flavia Pichiorri Nadia Carlesso Ya‐Huei Kuo Guido Marcucci Ling Li Jie Jin |
| author_sort | Huafeng Wang |
| collection | DOAJ |
| description | Abstract Background Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment. Methods We evaluated microRNA‐126 (miR‐126) levels in MDS patients’ sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs’ maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models. Results miR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients. Conclusions MiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS. |
| first_indexed | 2024-04-13T18:16:39Z |
| format | Article |
| id | doaj.art-0fb5de30591a4527baecf6716c3315b8 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-13T18:16:39Z |
| publishDate | 2021-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-0fb5de30591a4527baecf6716c3315b82022-12-22T02:35:39ZengWileyClinical and Translational Medicine2001-13262021-10-011110n/an/a10.1002/ctm2.610Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cellsHuafeng Wang0Jie Sun1Bin Zhang2Dandan Zhao3Hongyan Tong4Herman Wu5Xia Li6Yingwan Luo7Dan Dong8Yiyi Yao9Tinisha McDonald10Anthony S. Stein11Monzr M. Al Malki12Flavia Pichiorri13Nadia Carlesso14Ya‐Huei Kuo15Guido Marcucci16Ling Li17Jie Jin18Department of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaDepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USADepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USADepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaDepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USADepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USAHematological Malignancies Translational Science Gehr Family Center for Leukemia Research City of Hope Medical Center and Beckman Research Institute Duarte California USADepartment of Hematology the First Affiliated Hospital School of Medicine, Zhejiang University Hangzhou Zhejiang PR ChinaAbstract Background Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment. Methods We evaluated microRNA‐126 (miR‐126) levels in MDS patients’ sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs’ maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models. Results miR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients. Conclusions MiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS.https://doi.org/10.1002/ctm2.610CpG‐antimiR‐126HSPCsmiR‐126myelodysplastic syndrometransformation |
| spellingShingle | Huafeng Wang Jie Sun Bin Zhang Dandan Zhao Hongyan Tong Herman Wu Xia Li Yingwan Luo Dan Dong Yiyi Yao Tinisha McDonald Anthony S. Stein Monzr M. Al Malki Flavia Pichiorri Nadia Carlesso Ya‐Huei Kuo Guido Marcucci Ling Li Jie Jin Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells Clinical and Translational Medicine CpG‐antimiR‐126 HSPCs miR‐126 myelodysplastic syndrome transformation |
| title | Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| title_full | Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| title_fullStr | Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| title_full_unstemmed | Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| title_short | Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| title_sort | targeting mir 126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells |
| topic | CpG‐antimiR‐126 HSPCs miR‐126 myelodysplastic syndrome transformation |
| url | https://doi.org/10.1002/ctm2.610 |
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