Antagonistic Effect of CCAAT Enhancer-Binding Protein-α and Pax5 in Myeloid or Lymphoid Lineage Choice in Common Lymphoid Progenitors

Lymphoid lineage-committed progenitors, such as common lymphoid progenitors (CLPs), maintain a latent myeloid differentiation potential, which can be initiated by stimulation through exogenously expressed cytokine receptors, including IL-2 receptors. Here we show that the transcription factor CCAAT enhancerbinding protein-α (C/EBPα) is promptly up-regulated in CLPs upon ectopic IL-2 stimulation. Enforced C/EBPs expression is sufficient to initiate myeloid differentiation from CLPs, as well as from proT and proB cells, even though proB cells do not give rise to myeloid cells after ectopic IL-2 stimulation. Expression of Pax5, a B lymphoidaffiliated transcription factor, is completely suppressed by enforced C/EBPα but not by ectopic IL-2 stimulation in proB cells. Introduction of Pax5 blocks ectopic IL-2 receptor-mediated myeloid lineage conversion in CLPs. These data suggest that C/EBPα is a proximal target of cytokine-induced lineage conversion in lymphoid progenitors. Furthermore, complete loss of Pax5 expression triggered by up-regulation of C/EBPa is a critical event for lineage conversion from lymphoid to myeloid lineage in CLPs and proB cells.