CCAAT Enhancer Binding Protein-α (C/EBPα) Determines Myeloid Versus Erythroid Cell Fate in Multipotential Progenitors.

Abstract

C/EBPα is a bZip transcription factor, which is required for granulocyte development, and loss of C/EBPα function is associated with the development of acute myelogenous leukemia and myelodysplastic syndrome. While the precise mechanisms that regulate cell fate decisions during hematopoietic development are largely unknown, expression of transcription factors (PU.1 and GATA-1) can induce lineage conversion. In this regard, C/EBPα can drive the differentiation of B cells into macrophages, and bi-potential cell lines into granulocytes at the expense of macrophages. C/EBPα can also promote the transdifferentiation of myoblasts into adipocytes. We have recently found that there are increased numbers of erythroid cells in the fetal liver of C/EBPα −/ − mice. Also, C/EBPα is expressed in more primitive progenitor cells than granulocyte/macrophage progenitors (GMP) including hematopoietic stem cells. Therefore, we initiated experiments to evaluate whether C/EBPα has a functional role in regulating cell fate decisions in progenitors more primitive than GMP where it may promote a myeloid versus erythroid cell fate decision. To test this hypothesis, we over-expressed C/EBPα using retroviral vectors in 1) bone marrow cells (BMC) and evaluated their growth and differentiation in vitro, and in vivo when transplanted into mice; 2) purified multipotential progenitors with erythroid and myeloid potential, and erythroid restricted progenitors; and 3) murine erythroid leukemia (MEL) cells. We found that there was a marked decrease in erythroid lineage cells and an increase in myeloid cells in mice transplanted with BMC that over-expressed C/EBPα. We also observed a decrease in erythroid cell growth in vitro with BMC that expressed C/EBPα. Furthermore, when infected with retroviral vectors that express C/EBPα, erythroid restricted progenitors acquired myeloid cell morphology and myeloid specific cell surface markers. In addition, MEL cells that over-express C/EBPα showed increased myeloid gene expression including GM-CSFR, PR3 and myeloid specific esterase, while they showed decreased expression of β-globin and Epo receptor (EpoR) which is required for erythroid cell differentiation and survival. We detected high levels of EpoR in C/EBPα −/ − suggesting an inverse relationship between C/EBPα and EpoR expression. Thus, C/EBPα is a dual function transcription factor that can repress erythroid specific genes while enhancing myeloid lineage gene expression. Consequently, C/EBPα acts as a switch to drive hematopoietic progenitor cells toward myeloid cell development at the expense of erythroid maturation, and can reprogram erythroid cells into myeloid cells. # Funded in part by DHHS #NO1-CO-12400