Bcl-2 targeted overexpression into the erythroid lineage of transgenic mice delays but does not prevent the apoptosis of erythropoietin-deprived erythroid progenitors.
Erythropoietin (Epo) is known to control the erythroid developmental program through various biologic activities including maintenance of viability, cell proliferation, and/or cell maturation. In vitro experiments showed massive apoptosis in cultures of Epo-deprived colony-forming unit-erythroid (CFU-E) progenitors, demonstrating the Epo requirement of late-stage erythroid progenitors for survival. Based on these data, a model has been proposed whereby from CFU-E to proerythroblast stages, Epo acts rather as a survival factor than a proliferating factor. To investigate the relationship between Epo dependence and apoptotic mechanisms, we generated transgenic mice expressing the antiapoptotic human bcl-2 gene product in erythroid progenitors. Transgenic animals developed without any evidence of erythropoietic disorders. In vitro studies showed that overexpression of bcl-2 in erythroid progenitors delayed, but did not prevent the loss of CFU-E from Epo-deprivation. By measuring burst-forming unit-erythroid (BFU-E) and CFU-E-derived colonies, an enhanced sensitivity to low levels of Epo was demonstrated in adult bone marrow of transgenic mice with respect to nontransgenic animals. No spontaneous erythroid colonies were, however, observed in vitro in the absence of the cytokine, indicating that overexpression of bcl-2 is not sufficient to induce by itself a complete erythroid differentiation. Taken together, our data indicate that targeted erythroid overexpression of bcl-2 fails to alter the normal erythropoietic development in vivo and that erythroid progenitors remain strictly dependent on Epo for their survival.
Lacronique
V
V
Institut Cochin de Génétique Moléculaire, Université René Descartes, U 129 INSERM, Paris, France.
Varlet
P
P
Mayeux
P
P
Porteu
A
A
Gisselbrecht
S
S
Kahn
A
A
Lacombe
C
C
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000187:drug effects; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000378:metabolism; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D019076:Transgenes; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D019253:Proto-Oncogene Proteins c-bcl-2; D004921:Erythropoietin