LOSS OF ERYTHROPOIETIN RESPONSIVENESS IN ERYTHROID PROGENITORS DUE TOEXPRESSION OF THE EVI-1 MYELOID-TRANSFORMING GENE

Inappropriate expression of the Evi-1 zinc-finger gene in hematopoieti c cells has been associated with acute myelogenous leukemia and myelod ysplastic syndromes in murine models and in humans. Consistent with th is, previous studies have shown that aberrant expression of the Evi-1 gene in a myeloid progenitor cell line blocks granulocytic differentia tion. Here we demonstrate that the aberrant expression of the Evi-1 ge ne impairs the normal response of erythroid cells or bone-marrow proge nitors to erythropoietin. Erythroid differentiation has been shown to require the GATA-1 transcription factor that binds to a sequence conta ined within the consensus binding sequence identified for Evi-1. In th e studies presented here we also show that Evi-1 can repress GATA-1-de pendent transactivation in transient chloramphenicol acetyltransferase assays. Together the data support the hypothesis that inappropriate e xpression of the Evi-1 gene blocks erythropoiesis by repressing the tr anscription of a subset of GATA-1 target genes.