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Cytokine. 2020 Mar 19;130:155059. doi: 10.1016/j.cyto.2020.155059. [Epub ahead of print]

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

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.
2
Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
3
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
4
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia. Electronic address: Brendan.Jenkins@hudson.org.au.

Abstract

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.

KEYWORDS:

Hematopoiesis; Lymphopoiesis; Neutrophilia; STAT3; Serine phosphorylation; Splenomegaly; Thrombocytosis; Transcription

PMID:
32200265
DOI:
10.1016/j.cyto.2020.155059

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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