GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts.

Abstract

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-I down-regulation, whereas expression is maintained in erythroid, thrombocytic, and eosinophilic derivatives, prompted us to study the effect of forced GATA-I 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.

Transformation by v-Myb

“…Further studies revealed the multipotential nature of these transformed progenitor cells Moscovici et al, 1983a,b). Cell lines derived from these E26-transformed progenitors have proven very useful in dissecting the regulation of hematopoietic di erentiation (Kulessa et al, 1995;Rossi et al, 1996). Temperature-sensitive variants of the E26 virus have been isolated and molecularly characterized (Beug et al, 1984).…”

Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

“…The promiscuous expression of these lineage-specific markers has so frequently been observed in hematopoietic malignancies [5,6] that it is considered a hallmark of leukemia [5]. Furthermore, the switch between erythroid and myeloid lineages has also been reported on some transformed hematopoietic [7][8][9] and leukemic [10][11][12] cell lines. Taken together, these studies suggest that erythroid and myeloid development are closely associated in both normal hematopoiesis and hematopoietic disorders.…”

Reprogramming of human postmitotic neutrophils into macrophages by growth factors

“…Enforced expression of transcriptional factors such as GATA-1 and PU.1 leads to the lineage switch of myeloid cells to cells with another myeloid phenotype. [12][13][14][15][16][17] These lineage switches include myeloid to megakaryocytic, myeloid to eosinophilic, myeloid to erythroid, and erythroid to myeloid conversions. The ectopic expression of PU.1 and C/EBP also results in the commitment of hematopoietic progenitors to an eosinophilic lineage.…”