ABSENCE OF GRANULOCYTE-COLONY-STIMULATING FACTOR SIGNALING AND NEUTROPHIL DEVELOPMENT IN CCAAT ENHANCER-BINDING PROTEIN ALPHA-DEFICIENT MICE

Transcription factors are master regulatory switches of differentiatio n, including the development of specific hematopoietic lineages from s tem cells. Here we show that mice with targeted disruption of the CCAA T enhancer binding protein alpha gene (C/EBP alpha) demonstrate a sele ctive block in differentiation of neutrophils. Mature neutrophils and eosinophils are not observed in the blood or fetal liver of mutant ani mals, while other hematopoietic lineages, including monocytes, are not affected. Instead, most of the white cells in the peripheral blood of mutant mice had the appearance of myeloid blasts, We also observed a selective loss of expression of a critical gene target of CCAAT enhanc er binding protein alpha, the granulocyte colony-stimulating factor re ceptor. As a result, multipotential myeloid progenitors from the mutan t fetal liver are unable to respond to granulocyte colony-stimulating factor signaling, although they are capable of forming granulocyte-mac rophage and macrophage colonies in methylcellulose in response to othe r growth factors, Finally, we demonstrate that the lack of granulocyte development results from a defect intrinsic to the hematopoietic syst em; transplanted fetal liver from mutant mice can reconstitute lymphoi d hut not neutrophilic cells in irradiated recipients, These studies s uggest a model by which transcription factors can direct the different iation of multipotential precursors through activation of expression o f a specific growth factor receptor, allowing proliferation and differ entiation in response to a specific extracellular signal, In addition, the c/ebp alpha(-/-) mice may be useful in understanding the mechanis ms involved in acute myelogenous leukemia, in which a block in differe ntiation of myeloid precursors is a key feature of the disease.