Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis

Primary erythroid progenitors can be expanded by the synergistic action of erythropoietin (Epo), stem cell factor (SCF) and glucocorticoids, While Epo is required for erythropoiesis in general, glucocorticoids and SCF mainly contribute to stress erythropoiesis in hypoxic mice, This ability of normal erythroid progenitors to undergo expansion under stress conditions is targ eted by the avian erythroblastosis virus (AEV), harboring the oncogenes v-E rbB and v-ErbA, We investigated the signaling pathways required for progeni tor expansion under stress conditions and in leukemic transformation. Immor tal strains of erythroid progenitors, able to undergo normal, terminal diff erentiation under appropriate conditions, were established from fetal liver s of p53-/- mice. Expression and activation of the EGF-receptor (HER-1/c-Er bB) or its mutated oncogenic version (v-ErbB) in these cells abrogated the requirement for Epo and SCF in expansion of these progenitors and blocked t erminal differentiation. Upon inhibition of ErbB function, differentiation into erythrocytes occurred. Signal transducing molecules important for rene wal induction, i.e. Stat5- and phosphoinositide 3-kinase (PI3K), are utiliz ed by both EpoR/c-Kit and v/c-ErbB, However, while v-ErbB transformed cells and normal progenitors depended on PI3K signaling for renewal, c-ErbB also induces progenitor expansion by PI3K-independent mechanisms.