Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis.
Recurring chromosomal translocations observed in human leukemia often result in the expression of fusion proteins that are DNA-binding transcription factors. These altered proteins acquire new dimerization properties that result in the assembly of inappropriate multimeric transcription complexes that deregulate hematopoietic programs and induce leukemogenesis. Recently, we reported that the fusion protein AML1/MDS1/EVI1 (AME), a product of a t(3;21)(q26;q22) associated with chronic myelogenous leukemia and acute myelogenous leukemia, displays a complex pattern of self-interaction. Here, we show that the 8th zinc finger motif of MDS1/EVI1 is an oligomerization domain involved not only in interaction of AME with itself but also in interactions with the parental proteins, RUNX1 and MDS1/EVI1, from which AME is generated. Because the 8th zinc finger motif is also present in the oncoprotein EVI1, we have evaluated the effects of the interaction between RUNX1 and EVI1 in vitro and in vivo. We found that in vitro, this interaction alters the ability of RUNX1 to bind to DNA and to regulate a reporter gene, whereas in vivo, the expression of the isolated 8th zinc finger motif of EVI1 is sufficient to block the granulocyte colony-stimulating factor-induced differentiation of 32Dcl3 cells, leading to cell death. As EVI1 is not detected in normal bone marrow cells, these data suggest that its inappropriate expression could contribute to hematopoietic transformation in part by a new mechanism that involves EVI1 association with key hematopoietic regulators, leading to their functional impairment.
Senyuk
Vitalyi
V
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Sinha
Kislay K
KK
Li
Donglan
D
Rinaldi
Ciro R
CR
Yanamandra
Sastry
S
Nucifora
Giuseppina
G
D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016335:Zinc Fingers / Q000502:physiology
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C098704:MDS1-EVI1 fusion protein, human; C063575:MECOM protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors