C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx.

Objective: Mutations in the CCAAT enhancer binding protein epsilon (C/EBPepsilon) gene have been identified in the cells of patients with neutrophil specific granule deficiency, a rare congenital disorder marked by recurrent bacterial infections. Their neutrophils, in addition to lacking specific granules required for normal respiratory burst activity, also lack normal phagocytosis and chemotaxis. Although the specific granule deficiency phenotype has been replicated in C/EBPepsilon(-/-) (knockout [KO]) mice, the mechanisms by which C/EBPepsilon mutations act to decrease neutrophil function are not entirely clear.

Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBPepsilon gene.

Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder marked by recurrent bacterial infections. Neutrophils from SGD patients lack secondary and tertiary granules and their content proteins and lack normal neutrophil functions. Gene-inactivating mutations in the C/EBPepsilon gene have been identified in 2 SGD patients.

p120 nucleolar-proliferating antigen is a direct target of G-CSF signaling during myeloid differentiation.

Granulocyte-colony stimulating factor (G-CSF) is an essential cytokine, which contributes to proliferation and differentiation of granulocyte precursor cells in the bone marrow. Despite recent progress in understanding G-CSF signaling events, the mechanisms that underlie the distinct spectrum of biological functions attributed to G-CSF-mediated gene expression remain unclear. Previous studies have identified a number of genes, which are up-regulated in G-CSF-stimulated myeloid precursor cells.

Human neutrophil collagenase expression is C/EBP-dependent during myeloid development.

Objective: Human neutrophil collagenase (HNC) is one of several secondary granule proteins (SGP) expressed late in the myeloid maturation pathway. SGPs are encoded by unlinked and functionally diverse genes that are hypothesized to be coordinately regulated at the transcriptional level and demonstrate uniform dysregulation in leukemic cells. In support of the hypothesis that tissue and stage-specific expression of SGP genes is regulated by shared factor(s), we sought to identify factors responsible for positive regulation of the SGP genes.

G-CSF signaling can differentiate promyelocytes expressing a defective retinoic acid receptor: evidence for divergent pathways regulating neutrophil differentiation.

Several lines of investigation suggest that granulocyte colony-stimulating factor (G-CSF) augments all-trans retinoic acid (ATRA)-induced neutrophil differentiation in acute promyelocytic leukemia (APL). We sought to characterize the relationship between G-CSF- and ATRA-mediated neutrophil differentiation. We established a G-CSF receptor-transduced promyelocytic cell line, EPRO-Gr, derived from the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent EPRO cell line harboring a dominant-negative retinoic acid receptor alpha (RARalpha).

Chromatin immunoprecipitation (ChIP) studies indicate a role for CCAAT enhancer binding proteins alpha and epsilon (C/EBP alpha and C/EBP epsilon ) and CDP/cut in myeloid maturation-induced lactoferrin gene expression.

In vitro models of granulopoiesis involving the inducible expression of either CCAAT enhancer binding protein alpha (C/EBP alpha) or C/EBP epsilon in myeloid cells have been shown to lead to the induction of a granulocytic maturation program accompanied by the expression of myeloid-specific genes. Since members of the C/EBP family of transcription factors recognize and bind to similar DNA-binding motifs, it has been difficult to elucidate the specific role of each of the C/EBP family members in eliciting myeloid gene expression. In order to address this issue, we focused on the expression of the lactoferrin (LF) gene.