Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy
Abstract Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by r...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03499-w |
| _version_ | 1818576093764911104 |
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| author | Shiman Zuo Luchen Sun Yuxin Wang Bing Chen Jingyue Wang Xiangyu Ge Yan Lu Nanfei Yang Pingping Shen |
| author_facet | Shiman Zuo Luchen Sun Yuxin Wang Bing Chen Jingyue Wang Xiangyu Ge Yan Lu Nanfei Yang Pingping Shen |
| author_sort | Shiman Zuo |
| collection | DOAJ |
| description | Abstract Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML. |
| first_indexed | 2024-12-15T00:49:32Z |
| format | Article |
| id | doaj.art-3d23d2861acb4d81bda546b86823b138 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-15T00:49:32Z |
| publishDate | 2021-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-3d23d2861acb4d81bda546b86823b1382022-12-21T22:41:27ZengNature Publishing GroupCell Death and Disease2041-48892021-02-0112211510.1038/s41419-021-03499-wEstablishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapyShiman Zuo0Luchen Sun1Yuxin Wang2Bing Chen3Jingyue Wang4Xiangyu Ge5Yan Lu6Nanfei Yang7Pingping Shen8State Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityDepartment of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityDepartment of Pathology, Yale University School of MedicineState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of life science, Nanjing UniversityAbstract Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.https://doi.org/10.1038/s41419-021-03499-w |
| spellingShingle | Shiman Zuo Luchen Sun Yuxin Wang Bing Chen Jingyue Wang Xiangyu Ge Yan Lu Nanfei Yang Pingping Shen Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy Cell Death and Disease |
| title | Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy |
| title_full | Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy |
| title_fullStr | Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy |
| title_full_unstemmed | Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy |
| title_short | Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy |
| title_sort | establishment of a novel mesenchymal stem cell based regimen for chronic myeloid leukemia differentiation therapy |
| url | https://doi.org/10.1038/s41419-021-03499-w |
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