Abstract 3552: JAK/Stat3 signaling pathway modulates human megakaryocytic differentiation

Abstract Megakaryocytes (MKs) are differentiated from pluripotent hematopoietic stem cells toward a lineage capable of terminal differentiation to mature platelets. Various hematopoietic growth factors such as thrombopoietin, the ligand of c-mpl-encoded protein, have been identified as important regulators of MK development. Induction of MK differentiation may benefit disorders related to platelet dysfunction or thrombocytopenia. However, both effective inducer and clear mechanism of MK differentiation remain lacking. To clarify the regulatory mechanisms of MK differentiation, distinct inducers staurosporine (STS) and 12-O-Tetradecanoylphorbol-13-acetate (TPA) were used to assess the expression of Janus kinase (JAK) and Signal transducers and activators of transcription 3 (Stat3) signaling molecules in both human chronic myeloid leukemia K562 and erythroleukemia HEL cells. Our results demonstrated that STS and TPA effectively induced cell differentiation toward MK lineage in terms of development of polyploidy population, expression of MK-specific markers CD41 and CD61, and secretion of platelet factor 4. Intriguingly, enhancement in phosphorylation of Stat3 (p-Stat3), nuclear translocation and DNA-binding activity was evident in both STS- and TPA-treated cells. Blockade of Stat3 by Stat3 inhibitor VI and its upstream molecule JAK by JAK inhibitor I obviously declined MK differentiation. Furthermore, knockdown of Stat3 by RNA interference attenuated the expression of p-Stat3 and MK differentiation, indicating a crucial role of Stat3 in MK differentiation. In conclusion, JAK/Stat3 signaling pathway may involve MK differentiation and might be a target for development of therapeutic modulators for platelet disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3552. doi:10.1158/1538-7445.AM2011-3552