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Metabolic state of hematopoietic stem cells (HSCs) is an important regulator of self‐renewal and lineage‐specific differentiation. Posttranslational modification of proteins via  O ‐GlcNAcylation is an ideal metabolic sensor, but how it contributes to megakaryopoiesis and thrombopoiesis remains unknown. Here, we reveal for the first time that cellular  O ‐GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human‐derived hematopoietic stem and progenitor cells (HSPCs). Inhibition of  O ‐GlcNAc transferase (OGT) that catalyzes  O ‐GlcNAcylation prolongedly decreases  O ‐GlcNAcylation and induces the acquisition of CD34 + CD41a +  MK‐like progenitors and its progeny CD34 − CD41a + /CD42b +  megakaryoblasts (MBs)/MKs from HSPCs, consequently resulting in increased CD41a +  and CD42b +  platelets. Using correlation and co‐immunoprecipitation analyses, we further identify c‐Myc as a direct downstream target of  O ‐GlcNAcylation in MBs/MKs and provide compelling evidence on the regulation of platelets by novel  O ‐GlcNAc/c‐Myc axis. Our data indicate that  O ‐GlcNAcylation posttranslationally regulates c‐Myc stability by interfering with its ubiquitin‐mediated proteasomal degradation. Depletion of c‐Myc upon inhibition of OGT promotes platelet formation in part through the perturbation of cell adhesion molecules, that is, integrin‐α4 and integrin‐β7, as advised by gene ontology and enrichment analysis for RNA sequencing and validated herein. Together, our findings provide a novel basic knowledge on the regulatory role of  O ‐GlcNAcylation in megakaryopoiesis and thrombopoiesis that could be important in understanding hematologic disorders whose etiology are related to impaired platelet production and may have clinical applications toward an ex vivo platelet production for transfusion.

Metabolic sensor O‐ GlcNAcylation regulates megakaryopoiesis and thrombopoiesis through c‐Myc stabilization and integrin perturbation