Protein tyrosine phosphatase (PTPase) is critically involved in the regulation of hematopoietic stem cell development and differentiation. Roles of novel isolated receptor PTPase PTPRO from bone marrow hematopoietic stem cells in granulopoiesis have not been investigated. PTPRO expression is correlated with granulocytic differentiation, and Ptpro -/- mice developed neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors under steady-state and potentiated innate immune responses against Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling engaged glucose metabolism and initiated a transcriptional program involving the lineage decision factor C/EBPα, which is critically required for the PTPRO deficiency-directed granulopoiesis. Genetic ablation of mTOR or HIF1α or perturbation of glucose metabolism suppresses progenitor expansion, neutrophilia, and higher glycolytic activities by Ptpro -/- In addition, Ptpro -/- upregulated HIF1α regulates the lineage decision factor C/EBPα promoter activities. Thus, our findings identify a previously unrecognized interplay between receptor PTPase PTPRO signaling and mTOR-HIF1α metabolic reprogramming in progenitor cells of granulocytes that underlies granulopoiesis.
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