Induction of granulocytic differentiation by 2 pathways

The CCAAT enhancer binding protein α (C/EBPα) transcription factor plays a critical role in granulocytopoiesis. Mice with a disruption of the C/EBPα gene demonstrate an early block in granulocytic differentiation, and disruption of C/EBPα function is a common theme in many types of human acute myelogenous leukemia, which is characterized by a block in myeloid development. To characterize further the nature of this block, we derived cell lines from the fetal liver of C/EBPα-deficient animals. These lines resembled morphologically the immature myeloid blasts observed in C/EBPα^-/- fetal livers and did not express messenger RNA encoding early myeloid genes such as myeloperoxidase. Similarly, granulocytic markers such as Mac-1 and Gr-1 were not expressed; nor were erythroid and lymphoid surface antigens. Introduction of an inducible C/EBPα gene into the line revealed that conditional expression of C/EBPα induced the C/EBP family members C/EBPα and C/EBPε and subsequent granulocyte differentiation. Similar results were obtained when C/EBPα^-/- cells were stimulated with the cytokines interleukin-3 and granulocyte-macrophage colony-stimulating factor, but not with all-trans retinoic acid, supporting a model of at least 2 pathways leading to the differentiation of myeloid progenitors to granulocytes and implicating induction of other C/EBP family members in granulopoiesis.