Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells

• Published in: Cell death discovery 2023-07, Vol.9 (1), p.274-274, Article 274
• Main Authors: Zhang, Meichao, Meng, Yiling, Ying, Yingxia, Zhou, Pingting, Zhang, Suning, Fang, Yong, Yao, Yuan, Li, Dong
• Format: Article
• Language: English
• Subjects: 631/532/1542; 631/80/83; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell differentiation; Granulocyte colony-stimulating factor; Granulocyte-macrophage colony-stimulating factor; Leukocytes (neutrophilic); Life Sciences; Macrophages; Monocytes; Neutrophils; Overexpression; Phosphorylation; Progenitor cells; Stat3 protein; Stat5 protein; Stem Cells
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01575-y

The molecular programs that govern the directed differentiation of myeloid progenitor cells are still poorly defined. Using a previously established immortalized, phenotypically normal myeloid progenitor cell model mEB8-ER, we unveil a new mechanism mediated by STAT5 and STAT3 at a bifurcation point of myeloid progenitor cell-fate specification. We find that myeloid progenitor cells can spontaneously differentiate into neutrophils with a basal level of STAT3 phosphorylation, which is enhanced by G-CSF treatment or STAT3 over-expression, leading to elevated neutrophil differentiation. Reduced STAT3 phosphorylation caused by GM-CSF treatment, STAT3 specific inhibitor, or STAT3 depletion leads to attenuated myeloid differentiation into neutrophils, while elevating differentiation into monocytes/macrophages. In contrast, STAT5 appears to have an antagonistic function to STAT3. When activated by GM-CSF, STAT5 promotes myeloid differentiation into monocytes/macrophages but inhibits neutrophil differentiation. At the mechanistic level, GM-CSF activates STAT5 to up-regulate SOCS3, which attenuates STAT3 phosphorylation and consequently neutrophil differentiation, while enhancing monocyte/macrophage differentiation. Furthermore, inhibition of STAT5 and STAT3 in primary myeloid progenitors recapitulates the results from the mEB8-ER model. Together, our findings provide new mechanistic insights into myeloid differentiation and may prove useful for the diagnosis and treatment of diseases related to abnormal myeloid differentiation.