title: Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells.
abstract: Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor that plays an essential role in the regulation of hematopoietic stem cells. Aberrant expression of Evi-1 has been reported in up to 10% of patients with acute myeloid leukemia and is a diagnostic marker that predicts a poor outcome. Although chromosomal rearrangement involving the Evi-1 gene is one of the major causes of Evi-1 activation, overexpression of Evi-1 is detected in a subgroup of acute myeloid leukemia patients without any chromosomal abnormalities, which indicates the presence of other mechanisms for Evi-1 activation. In this study, we found that Evi-1 is frequently up-regulated in bone marrow cells transformed by the mixed-lineage leukemia (MLL) chimeric genes MLL-ENL or MLL-AF9. Analysis of the Evi-1 gene promoter region revealed that MLL-ENL activates transcription of Evi-1. MLL-ENL-mediated up-regulation of Evi-1 occurs exclusively in the undifferentiated hematopoietic population, in which Evi-1 particularly contributes to the propagation of MLL-ENL-immortalized cells. Furthermore, gene-expression analysis of human acute myeloid leukemia cases demonstrated the stem cell-like gene-expression signature of MLL-rearranged leukemia with high levels of Evi-1. Our findings indicate that Evi-1 is one of the targets of MLL oncoproteins and is selectively activated in hematopoietic stem cell-derived MLL leukemic cells.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.forename: Munetake
authors.initials: M
authors.lastname: Shimabe
authors.forename: Motoshi
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.forename: Susumu
authors.initials: S
authors.lastname: Goyama
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008817:Mice, Mutant Strains; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein