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

CCAAT/enhancer binding protein epsilon (C/EBP epsilon) is essential for ter minal granulocytic differentiation. Its expression begins at the transition between the proliferative and non-proliferative compartments of myelopoies is, 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/EB P epsilon -/- mice had an expansion in the number of their CFU-GM/femur, Th e 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. How ever, the number of myeloid colonies arising from purified Sca-1+/lin- earl y hematopoietic progenitor cells and from bone marrow mononuclear cells gro wn in different cytokine combinations was not significantly different betwe en wild-type and knock-out mice. Also, long-term marrow growth, and CFU wer e not different between the wild-type and C/EBP epsilon -/- mice. The sensi tivity to induction of apoptosis in the committed progenitor cell compartme nt after either withdrawal of growth factor or brief exposure to etoposide was normal. However, Gr-l antigen-positive C/EBP epsilon -/- granulocytic c ells showed an increased rate of apoptosis in comparison to their wild-type counterparts. In summary, the myeloid compartment appears to be expanded i n mice lacking C/EBP epsilon, However, this is not the consequence of an in trinsic myeloproliferation but due to an indirect, possibly cytokine-mediat ed stimulation of myelopoiesis in vivo. C/EBP epsilon may have a role in th e inhibition of apoptosis in maturing granulocytic cells.