C/EBPε −/− mice: increased rate of myeloid proliferation and apoptosis

Abstract

CCAAT/enhancer binding protein epsilon (C/EBP⑀) is essential for terminal granulocytic differentiation. Its expression begins at the transition between the proliferative and non-proliferative compartments of myelopoiesis. We studied the effect of targeted disruption of the C/EBP⑀ gene on murine myeloid proliferation and apoptosis. Bone marrow cellularity of C/EBP⑀ −/− and wild-type mice was 95% and 65%, respectively. The C/EBP⑀ −/− mice had an expansion in the number of their CFU-GM/femur. The number of myeloid committed progenitor cells in the peripheral blood and the spleen of these mice was also increased. Bromodeoxyuridine (BrDU) pulse labeling studies demonstrated that the fraction of actively proliferating cells was two-fold higher in the bone marrow of C/EBP⑀ −/− mice. However, the number of myeloid colonies arising from purified Sca-1+/lin− early hematopoietic progenitor cells and from bone marrow mononuclear cells grown in different cytokine combinations was not significantly different between wild-type and knock-out mice. Also, long-term marrow growth, and CFU were not different between the wild-type and C/EBP⑀ −/− mice. The sensitivity to induction of apoptosis in the committed progenitor cell compartment after either withdrawal of growth factor or brief exposure to etoposide was normal. However, Gr-1 antigen-positive C/EBP⑀ −/− granulocytic cells showed an increased rate of apoptosis in comparison to their wild-type counterparts. In summary, the myeloid compartment appears to be expanded in mice lacking C/EBP⑀. However, this is not the consequence of an intrinsic myeloproliferation but due to an indirect, possibly cytokine-mediated stimulation of myelopoiesis in vivo. C/EBP⑀ may have a role in the inhibition of apoptosis in maturing granulocytic cells. Leukemia (2001) 15, 103-111.

miRNA-130a regulates C/EBP-ε expression during granulopoiesis

“…As mentioned above, cell cycle progression is also regulated by C/EBP-e. 4,10 Targeted deletion of Cebpe is known to induce a block in differentiation at the myelocyte stage causing more cells to be retained in the proliferative stage. 4 Conversely, forced expression of C/EBP-e drives more cells into the G 0 /G 1 -phase of cell cycle, resulting in decreased proliferation and enhanced differentiation.…”

“…3 CCAAT/enhancer binding protein-e (C/EBP-e) is a transcription factor essential for terminal granulopoiesis. 4 The C/EBPs constitute a family of highly conserved transcription factors with 6 members (C/EBP-a, -b, -d, -e, -g, and -z) that bind to DNA via a leucine zipper domain. 5 All members are expressed at some stage during neutrophil development, but not all at the same time.…”

Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors

“…C/EBPε-null mice are viable but lack functional neutrophils and eosinophils, and eventually develop myelodysplasia (Verbeek et al, 2001;Yamanaka et al, 1997). Conversely, forced expression of C/EBPε induces differentiation of promyelocytic leukemia cells (LekstromHimes, 2001;Truong et al, 2003).…”

Human C/EBP-ϵ activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation

“…7,9,10 C/EBP-⑀-null mice lack mature functional granulocytes (both neutrophils and eosinophils), and the mice die by 3 to 5 months of age because of opportunistic infections. 7,11 Similarly, patients with a frame-shift mutation in the C/EBP-⑀ gene suffer from specific granulocyte deficiency disease, characterized by recurrent pyogenic infections, defective neutrophil chemotaxis, and bactericidal activity, and lack of neutrophil secondary granule proteins. 12 Eosinophils in these patients also lack secondary granule proteins and are functionally impaired.…”