THE ESTROGEN-RECEPTOR COOPERATES WITH THE TGF-ALPHA RECEPTOR (C-ERBB) IN REGULATION OF CHICKEN ERYTHROID PROGENITOR SELF-RENEWAL

A unique combination of growth promoting factors is described that allows growth of large amounts (10(10)-10(11)) of normal erythroid progenitors from chick bone marrow. These erythroid progenitors express the estrogen receptor (ER) as well as the receptor tyrosine kinase TGFalpha/c-erbB. They require both TGFalpha and estradiol for sustained self-renewal in vitro, but terminally differentiate upon withdrawal of TGFalpha and inactivation of the ER by an antagonist (ICI 164.384). Overexpression of the human ER in erythroblasts devoid of endogenous ER revealed that the hormone-activated ER alone arrested erythroid differentiation and repressed a large group of erythrocyte genes. When similarly overexpressed, TGFalphaR/c-erbB inhibited the expression of a distinct, but overlapping, set of genes. The endogenous ER and TGFalphaR/c-erbB affect erythrocyte gene expression in a similar, but less pronounced fashion. Surprisingly, suppression of ER function by antagonist efficiently inhibited erythroblast transformation by tyrosine kinase oncogenes, suggesting a role of the endogenous ER in leukemogenesis. We speculate that the oncogenes v-erbB and v-erbA cooperate in erythroleukemia induction by a mechanism that is employed by TGFalphaR/c-erbB and ER to regulate normal progenitor self-renewal in response to external signals.