Aurka loss in CD19+ B cells promotes megakaryocytopoiesis via IL-6/STAT3 signaling-mediated thrombopoietin production
| Autor: | Takayuki Ikezoe, Hui Wang, Xin Chen, Hongbin Qiu, Jing Han, Rongqing Li, Yangyang Tang, Jie Zhao, Chennan Wang, Huan Tong, Xueqin Li, Na Sun, Shuai Pan, Jianlin Qiao, Jing Yang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Megakaryocyte differentiation Medicine (miscellaneous) Aurora-A megakaryocytopoiesis CD19 STAT3 03 medical and health sciences 0302 clinical medicine medicine thrombopoietin Autocrine signalling Pharmacology Toxicology and Pharmaceutics (miscellaneous) Thrombopoietin B cell Megakaryocytopoiesis IL-6 biology Chemistry Cell biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Aurora Kinase A Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Rationale: Aurora kinase A (Aurora-A), which is required for mitosis, is a therapeutic target in various tumors. Targeting Aurora-A led to an increase in the differentiation and polyploidization of megakaryocytes both in vivo and in vitro. However, the mechanisms involved in controlling megakaryocyte differentiation have not been fully elucidated. Methods: Conditional Aurka knockout mice were generated. B cell development, platelet development and function were subsequently examined. Proplatelet formation, in vivo response to mTPO, post-transfusion experiment, colony assay, immunofluorescence staining and quantification, and ChIP assay were conducted to gain insights into the mechanisms of Aurka loss in megakaryocytopoiesis. Results: Loss of Aurka in CD19+ B cells impaired B cell development in association with an increase in the number of platelets in peripheral blood (PB). Surprisingly, thrombopoietin (TPO) production and IL-6 were elevated in the plasma in parallel with an increase in the number of differentiated megakaryocytes in the bone marrow (BM) of Aurkaf/f;Cd19Cre/+ mice. Interestingly, compared with that of the Aurkaf/f mice, a higher number of CD19+ B cells close to megakaryocytes was observed in the BM of the Aurkaf/f;Cd19Cre/+ mice. Moreover, Aurka loss in CD19+ B cells induced signal transducer and activator of transcription-3 (STAT3) activation. Inhibition of STAT3 reduced the Tpo mRNA levels. ChIP assays revealed that STAT3 bound to the TPO promoter. Additionally, STAT3-mediated TPO transcription was an autocrine effect provoked by IL-6, at least partially. Conclusions: Deletion of Aurka in CD19+ B cells led to an increase in IL-6 production, promoting STAT3 activation, which in turn contributed to TPO transcription and megakaryocytopoiesis. |
| Databáze: | OpenAIRE |
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