Erythropoietin (EPO) and its receptor (EPOR) are required for the developme
nt of mature erythrocytes. After binding of ligand, the EPOR activates a va
riety of signaling pathways that ultimately control cellular proliferation,
survival, and specific gene expression. Although erythroid progenitors app
ear to be the principal EPO-responsive cell type in vivo due to the restric
ted expression of the EPOR, many growth factor-dependent cell lines express
ing the EPOR can respond to EPO by activating many or all of these pathways
. In the present study, we have identified a cellular context (the interleu
kin-2 [IL-2]-dependent HT-2 line) in which the EPO stimulation of the EPOR
fails to support cellular proliferation, STAT-5 induction, or MAPK activati
on, despite efficient phosphorylation of the EPOR and JAK2 and inhibition o
f apoptosis after withdrawal of IL-2. Interestingly, when we fused HT-2 cel
ls expressing the EPOR with Ba/F3 cells in a complementation assay, the res
ulting hybridomas proliferated and potently activated STAT-5 and MAPK in re
sponse to EPO. These data indicate that an unidentified cellular factor is
needed to mediate signaling by the EPOR. Moreover, Ba/F3 cells apparently e
xpress this factor(s) and somatic fusions can, therefore, confer EPO respon
siveness to HT-2 cells that lack this factor. (C) 1999 by The American Soci
ety of Hematology.