Deregulated activation of the latent transcription factor STAT3 has been implicated in the pathogenesis of myeloproliferative and lymphoproliferative hematologic disorders. The uncontrolled activation of STAT3 has traditionally been assigned to its elevated phosphorylation at tyrosine 705 (pY705) and associated nuclear transcriptional activity. By contrast, a transcriptional role for serine 727 phosphorylation (pS727) of STAT3 has recently emerged, suggesting that pS727 may account for the pathological activity of STAT3 in certain disease settings. Here, by coupling pS727-STAT3-deficient Stat3SA/SA mice with a STAT3-driven mouse model (gp130F/F) for myeloproliferative and lymphoproliferative pathologies, we reveal a key role for pS727-STAT3 in promoting multiple hematologic pathologies. The genetic blockade of pS727-STAT3 in gp130F/F:Stat3SA/SA mice ameliorated the neutrophilia, thrombocytosis, splenomegaly and lymphadenopathy that are features of gp130F/F mice. The protection against thrombocytosis in gp130F/F:Stat3SA/SA mice coincided with normalized megakaryopoiesis in both bone marrow and spleen compartments. Interestingly, pS727-STAT3-mediated abnormal lymphopoiesis in gp130F/F mice was more pronounced in lymph nodes compared to thymus, and was characterized by elevated numbers of B cells at the expense of T cells. Furthermore, pS727-STAT3 dependency for these hematologic pathologies coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic genes. Collectively, these findings suggest that pS727 plays a critical pathological role in modulating the transcriptional activity of STAT3 in hematologic disorders.

中文翻译：

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STAT3 驱动的造血和淋巴细胞生成异常依赖于丝氨酸磷酸化

潜伏转录因子 STAT3 的失调激活与骨髓增生性和淋巴增生性血液病的发病机制有关。STAT3 不受控制的激活传统上被归因于其酪氨酸 705 (pY705) 的磷酸化升高和相关的核转录活性。相比之下，最近出现了 STAT3 丝氨酸 727 磷酸化 (pS727) 的转录作用，这表明 pS727 可能解释了某些疾病环境中 STAT3 的病理活性。在这里，通过将 pS727-STAT3 缺陷 Stat3SA/SA 小鼠与 STAT3 驱动的小鼠模型 (gp130F/F) 结合用于骨髓增殖和淋巴组织增生病理，我们揭示了 pS727-STAT3 在促进多种血液病理方面的关键作用。gp130F/F 中 pS727-STAT3 的基因阻断：Stat3SA/SA 小鼠改善了 gp130F/F 小鼠的中性粒细胞增多、血小板增多、脾肿大和淋巴结病。gp130F/F:Stat3SA/SA 小鼠对血小板增多症的保护作用与骨髓和脾脏区室中的标准化巨核细胞生成一致。有趣的是，与胸腺相比，gp130F/F 小鼠的 pS727-STAT3 介导的异常淋巴细胞生成在淋巴结中更为明显，其特点是 B 细胞数量增加而 T 细胞减少。此外，这些血液病学的 pS727-STAT3 依赖性与对 STAT3 调节基因的转录活性一致，而不是对线粒体和代谢基因的影响。总的来说，这些发现表明 pS727 在调节 STAT3 在血液疾病中的转录活性方面起着关键的病理作用。