Theranostics 2021; 11(10):4655-4671. doi:10.7150/thno.49007 This issue

Research Paper

Aurka loss in CD19+ B cells promotes megakaryocytopoiesis via IL-6/STAT3 signaling-mediated thrombopoietin production

Xin Chen1,2*, Chennan Wang3*, Na Sun1,2, Shuai Pan1,2, Rongqing Li1,2, Xueqin Li1,2, Jie Zhao1,2, Huan Tong4, Yangyang Tang1,2, Jing Han1,2, Jianlin Qiao4, Hongbin Qiu3, Hui Wang1,2,5✉, Jing Yang1,2,5✉, Takayuki Ikezoe6

1. Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China.
2. Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
3. School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
4. Department of Hematology, The First Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
5. National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
6. The Department of Hematology, Fukushima Medical University, Fukushima, Japan.
*Equal contribution

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chen X, Wang C, Sun N, Pan S, Li R, Li X, Zhao J, Tong H, Tang Y, Han J, Qiao J, Qiu H, Wang H, Yang J, Ikezoe T. Aurka loss in CD19+ B cells promotes megakaryocytopoiesis via IL-6/STAT3 signaling-mediated thrombopoietin production. Theranostics 2021; 11(10):4655-4671. doi:10.7150/thno.49007. Available from https://www.thno.org/v11p4655.htm

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Abstract

Graphic abstract

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.

Keywords: Aurora-A, thrombopoietin, STAT3, IL-6, megakaryocytopoiesis.