C/EBP epsilon directs granulocytic versus monocytic lineage determination and confers chemotactic function via Hlx. Experimental hematology [Exp Hematol] Journal article

OBJECTIVE: Mutations in the C/EBPepsilon gene have been identified in the cells of patients with neutrophil specific granule deficiency (SGD), 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 SGD phenotype has been replicated in C/EBPepsilon(-/-) (KO) mice, the mechanisms by which C/EBPepsilon mutations act to decrease neutrophil function are not entirely clear.
METHODS: In order to determine the role of C/EBPepsilon in neutrophil differentiation and migration, we generated immortalized progenitor cell lines from C/EBPepsilon KO and wild type (WT) mice and performed expression and flow cytometric analysis and functional studies.
RESULTS: Expression of lineage specific cell surface antigens on our in vitro differentiated cell lines revealed persistent expression of monocytic markers on KO granulocytes. We verified this in primary murine peripheral blood and bone marrow cells. In addition, KO BM had an increase in immature myeloid precursors at the common myeloid progenitor (CMP) and granulocyte monocyte progenitor (GMP) level suggesting a critical role for C/EBPepsilon not only in granulocyte maturation beyond the promyelocyte stage, but also in the monocyte/granulocyte lineage decision. We found that restoration of Hlx (H2.0-like homeo box 1) expression, which was decreased in C/EBPepsilon KO cells, rescued chemotaxis, but not the other defects of C/EBPepsilon KO neutrophils.

Experimental hematology [Exp Hematol]