Loss of erythropoietin responsiveness in erythroid progenitors due to expression of the Evi-1 myeloid-transforming gene.
Inappropriate expression of the Evi-1 zinc-finger gene in hematopoietic cells has been associated with acute myelogenous leukemia and myelodysplastic syndromes in murine models and in humans. Consistent with this, previous studies have shown that aberrant expression of the Evi-1 gene in a myeloid progenitor cell line blocks granulocytic differentiation. Here we demonstrate that the aberrant expression of the Evi-1 gene impairs the normal response of erythroid cells or bone-marrow progenitors to erythropoietin. Erythroid differentiation has been shown to require the GATA-1 transcription factor that binds to a sequence contained within the consensus binding sequence identified for Evi-1. In the studies presented here we also show that Evi-1 can repress GATA-1-dependent transactivation in transient chloramphenicol acetyltransferase assays. Together the data support the hypothesis that inappropriate expression of the Evi-1 gene blocks erythropoiesis by repressing the transcription of a subset of GATA-1 target genes.
Kreider
B L
BL
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105.
Orkin
S H
SH
Ihle
J N
JN
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000254:growth & development; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D004921:Erythropoietin / Q000494:pharmacology*; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D004921:Erythropoietin