STAT3-driven hematopoiesis and lymphopoiesis abnormalities are dependent on serine phosphorylation

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 Stat3^SA/SA mice with a STAT3-driven mouse model (gp130^F/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 gp130^F/F:Stat3^SA/SA mice ameliorated the neutrophilia, thrombocytosis, splenomegaly and lymphadenopathy that are features of gp130^F/F mice. The protection against thrombocytosis in gp130^F/F:Stat3^SA/SA mice coincided with normalized megakaryopoiesis in both bone marrow and spleen compartments. Interestingly, pS₇₂₇-STAT3-mediated abnormal lymphopoiesis in gp130^F/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.