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

CCAAT/enhancer binding protein epsilon (C/EBP epsilon) 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 epsilon gene on murine myeloid proliferation and apoptosis, Bone marrow cellularity of C/EBP epsilon -/- and wild-type mice was 95% and 65%, respectively. The C/EBP epsilon -/- 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 epsilon -/- 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 epsilon -/- 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-l antigen-positive C/EBP epsilon -/- 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 epsilon, 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 epsilon may have a role in the inhibition of apoptosis in maturing granulocytic cells.