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

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 Aurka ^f/f ;Cd19 ^Cre/+ mice. Interestingly, compared with that of the Aurka ^f/f mice, a higher number of CD19 ⁺ B cells close to megakaryocytes was observed in the BM of the Aurka ^f/f ;Cd19 ^Cre/+ 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.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)