c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance
Abstract Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberr...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05315-5 |
| _version_ | 1811238768444702720 |
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| author | Fei Li Yuanyan Xiong Mo Yang Peiling Chen Jingkai Zhang Qiong Wang Miao Xu Yiming Wang Zuyong He Xin Zhao Junyu Huang Xiaoqiong Gu Li Zhang Rui Sun Xunsha Sun Jingyao Li Jinxin Ou Ting Xu Xueying Huang Yange Cao Xiaohong Ruby Xu Danielle Karakas June Li Heyu Ni Qing Zhang |
| author_facet | Fei Li Yuanyan Xiong Mo Yang Peiling Chen Jingkai Zhang Qiong Wang Miao Xu Yiming Wang Zuyong He Xin Zhao Junyu Huang Xiaoqiong Gu Li Zhang Rui Sun Xunsha Sun Jingyao Li Jinxin Ou Ting Xu Xueying Huang Yange Cao Xiaohong Ruby Xu Danielle Karakas June Li Heyu Ni Qing Zhang |
| author_sort | Fei Li |
| collection | DOAJ |
| description | Abstract Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored. Here, we identified increased expression of a c-Mpl alternative splicing isoform, c-Mpl-del, in AMKL patients. We found that c-Mpl-del expression was associated with enhanced AMKL cell proliferation and chemoresistance, and decreased survival in xenografted mice, while c-Mpl-del knockdown attenuated proliferation and restored apoptosis. Interestingly, we observed that c-Mpl-del exhibits preferential utilization of phosphorylated c-Mpl-del C-terminus Y607 and biased activation of PI3K/AKT pathway, which culminated in upregulation of GATA1 and downregulation of DDIT3-related apoptotic responses conducive to AMKL chemoresistance and proliferation. Thus, this study elucidates the critical roles of c-Mpl alternative splicing in AMKL progression and drug resistance, which may have important diagnostic and therapeutic implications for leukemia accelerated by c-Mpl-del overexpression. |
| first_indexed | 2024-04-12T12:48:01Z |
| format | Article |
| id | doaj.art-3383a1f7b8b6488b95e683aa62eba876 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T12:48:01Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-3383a1f7b8b6488b95e683aa62eba8762022-12-22T03:32:34ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011210.1038/s41419-022-05315-5c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistanceFei Li0Yuanyan Xiong1Mo Yang2Peiling Chen3Jingkai Zhang4Qiong Wang5Miao Xu6Yiming Wang7Zuyong He8Xin Zhao9Junyu Huang10Xiaoqiong Gu11Li Zhang12Rui Sun13Xunsha Sun14Jingyao Li15Jinxin Ou16Ting Xu17Xueying Huang18Yange Cao19Xiaohong Ruby Xu20Danielle Karakas21June Li22Heyu Ni23Qing Zhang24State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityThe Seventh Affiliated Hospital, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityDepartment of Laboratory Medicine and Pathobiology, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University of TorontoState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityDepartment of Blood Transfusion, Clinical Biological Resource Bank and Clinical Lab, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityDepartment of Blood Transfusion, Clinical Biological Resource Bank and Clinical Lab, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer CenterNational Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityDepartment of Laboratory Medicine and Pathobiology, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University of TorontoState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityAbstract Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored. Here, we identified increased expression of a c-Mpl alternative splicing isoform, c-Mpl-del, in AMKL patients. We found that c-Mpl-del expression was associated with enhanced AMKL cell proliferation and chemoresistance, and decreased survival in xenografted mice, while c-Mpl-del knockdown attenuated proliferation and restored apoptosis. Interestingly, we observed that c-Mpl-del exhibits preferential utilization of phosphorylated c-Mpl-del C-terminus Y607 and biased activation of PI3K/AKT pathway, which culminated in upregulation of GATA1 and downregulation of DDIT3-related apoptotic responses conducive to AMKL chemoresistance and proliferation. Thus, this study elucidates the critical roles of c-Mpl alternative splicing in AMKL progression and drug resistance, which may have important diagnostic and therapeutic implications for leukemia accelerated by c-Mpl-del overexpression.https://doi.org/10.1038/s41419-022-05315-5 |
| spellingShingle | Fei Li Yuanyan Xiong Mo Yang Peiling Chen Jingkai Zhang Qiong Wang Miao Xu Yiming Wang Zuyong He Xin Zhao Junyu Huang Xiaoqiong Gu Li Zhang Rui Sun Xunsha Sun Jingyao Li Jinxin Ou Ting Xu Xueying Huang Yange Cao Xiaohong Ruby Xu Danielle Karakas June Li Heyu Ni Qing Zhang c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance Cell Death and Disease |
| title | c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance |
| title_full | c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance |
| title_fullStr | c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance |
| title_full_unstemmed | c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance |
| title_short | c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance |
| title_sort | c mpl del a c mpl alternative splicing isoform promotes amkl progression and chemoresistance |
| url | https://doi.org/10.1038/s41419-022-05315-5 |
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