We have continued define the molecular events that regulate hematopoietic stem cell (HSC) quiescence, survival, self-renewal and, myeloid cell lineage commitment and differentiation. We have focused our efforts on transcription factors since they are essential for stem cell and lineage development by regulating the expression of hematopoietic growth factors (HGF), HGF receptors, other transcription factors, and lineage specific genes. We have discovered that hematopoietic progenitors that lack C/EBP-alpha show increased erythroid growth in vitro and in vivo suggesting that C/EBP-alpha may negatively regulate erythroid differentiation. In comparison, we found a marked decrease in erythroid lineage cells and an increase in myeloid cells in mice transplanted with BMC infected with retroviral vectors that express C/EBP-alpha. We also observed a decrease in erythroid cell growth in vitro with BMC that over-express C/EBP-alpha. Normal erythroid restricted progenitors acquire myeloid cell morphology and myeloid specific cell surface markers when infected with retroviral vectors that express C/EBP-alpha. In addition, erythroid cell lines that over-express C/EBP-alpha show increased myeloid gene expression, and decreased expression of Epo receptor (EpoR), which is required for erythroid cell differentiation and survival. We detected high levels of EpoR in C/EBP-alpha null mice suggesting an inverse relationship between C/EBPa and EpoR expression. Thus, C/EBPa is a dual function transcription factor that can repress erythroid specific genes while enhancing myeloid lineage gene expression. Altogether, we propose that C/EBPa acts as a switch to drive hematopoietic progenitor cells toward a myeloid cell development at the expense of erythroid maturation, and can reprogram erythroid cells to differentiate into myeloid cells.
Showing the most recent 10 out of 18 publications
