GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts.
The transcription factor GATA-1 is expressed in early hematopoietic progenitors and specifically down-regulated in myelomonocytic cells during lineage determination. Our earlier observation that the differentiation of Myb-Ets-transformed chicken hematopoietic progenitors into myeloblasts likewise involves a GATA-1 down-regulation, whereas expression is maintained in erythroid, thrombocytic, and eosinophilic derivatives, prompted us to study the effect of forced GATA-1 expression in Myb-Ets-transformed myeloblasts. We found that the factor rapidly suppresses myelomonocytic markers and induces a reprogramming of myeloblasts into cells resembling either transformed eosinophils or thromboblasts. In addition, we observed a correlation between the level of GATA-1 expression and the phenotype of the cell, intermediate levels of the factor being expressed by eosinophils and high levels by thromboblasts, suggesting a dosage effect of the factor. GATA-1 can also induce the formation of erythroblasts when expressed in a myelomonocytic cell line transformed with a Myb-Ets mutant containing a lesion in Ets. These cells mature into erythrocytes following temperature-inactivation of the Ets protein. Finally, the factor can reprogram a v-Myc-transformed macrophage cell line into myeloblasts, eosinophils, and erythroblasts, showing that the effects of GATA-1 are not limited to Myb-Ets-transformed myeloblasts. Our results suggest that GATA-1 is a lineage-determining transcription factor in transformed hematopoietic cells, which not only activates lineage-specific genetic programs but also suppresses myelomonocytic differentiation. They also point to a high degree of plasticity of transformed hematopoietic cells.
Kulessa
H
H
Differentiation Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Frampton
J
J
Graf
T
T
D000818:Animals; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology*; D002454:Cell Differentiation; D002645:Chickens; D004268:DNA-Binding Proteins / Q000502:physiology*; D004804:Eosinophils / Q000166:cytology*; D004900:Erythroblasts / Q000737:chemistry*; D050981:Erythroid-Specific DNA-Binding Factors; D004958:Estradiol / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D016335:Zinc Fingers
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D014157:Transcription Factors; D004958:Estradiol; D016186:Receptor, Macrophage Colony-Stimulating Factor