Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-X(L) and Bcl-2

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-X(L) but not Bar were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-X(L) or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo, Furthermore, endogenous levels of bcl-2 and bcl-X(L) were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-X(L), further indicating that Epo specifically maintains the expression of bcl-2 and bcl-chi(L). We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-X(L) can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-X(L) and Bcl-2 during proliferation and differentiation of erythroid progenitors. (C) 1996 by The American Society of Hematology.