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 targeted by the avian erythroblastosis virus (AEV), harboring the oncogenes v-ErbB and v-ErbA. We investigated the signaling pathways required for progenitor expansion under stress conditions and in leukemic transformation. Immortal strains of erythroid progenitors, able to undergo normal, terminal differentiation under appropriate conditions, were established from fetal livers of p53-/- mice. Expression and activation of the EGF-receptor (HER-1/c-ErbB) or its mutated oncogenic version (v-ErbB) in these cells abrogated the requirement for Epo and SCF in expansion of these progenitors and blocked terminal differentiation. Upon inhibition of ErbB function, differentiation into erythrocytes occurred. Signal transducing molecules important for renewal induction, i.e. Stat5- and phosphoinositide 3-kinase (PI3K), are utilized 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.
von Lindern
M
M
Institute of Hematology, Erasmus Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Deiner
E M
EM
Dolznig
H
H
Parren-Van Amelsvoort
M
M
Hayman
M J
MJ
Mullner
E W
EW
Beug
H
H
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000473:pathology*; D004920:Erythropoiesis; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018739:Oncogene Proteins v-erbB / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D018739:Oncogene Proteins v-erbB; D017467:Receptors, Erythropoietin; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit