Nucleotides, which bind to P2 receptors, have emerged as a family of mediators in intercellular communication. P2X7 is a member of the P2X family ligand-gated ion channels respond to extracellular ATP. High level expression of P2X7 was detected in leukemia samples, especially in relapsed cases. However, the role of P2X7 mediated signaling in hematopoietic stem/progenitor cells (HSPCs) as well as its potential role in leukemogenesis have not been established. In this study, the expression of P2X7 in hematopoietic cells in different lineages and stages was analyzed. Over-expression of P2X7 in HSPCs was carried out by retrovirus infection to study the impact on HSPCs. The results showed that low level expression of P2X7 was detected in HSPCs. Over-expression of P2X7 in HSPCs resulted in decreased colony forming ability in vitro and engraftment potential in vivo. These results suggested that high level purinergic signaling by P2X7 impaired function of HSPCs.