The t(3;21) fusion product, AML1/Evi-1 blocks AML1-induced transactivation by recruiting CtBP.
AML1/Evi-1 is a chimeric protein that is derived from t(3;21), found in blastic transformation of chronic myelogenous leukemia. It is composed of the N-terminal AML1 portion with the DNA-binding Runt domain and the C-terminal Evi-1 portion. It has been shown to dominantly repress AML1-induced transactivation. The mechanism for it has been mainly attributed to competition with AML1 for the DNA-binding and for the interaction with PEBP2beta (CBFbeta), a partner protein which heterodimerizes with AML1. It was recently found that Evi-1 interacts with C-terminal binding protein (CtBP) to repress TGFbeta-induced transactivation. Here, we demonstrate that AML1/Evi-1 interacts with CtBP in SKH1 cells, a leukemic cell line which endogenously overexpresses AML1/Evi-1 and that AML1/Evi-1 requires the interaction with CtBP to repress AML1-induced transactivation. The association with CtBP is also required when AML1/Evi-1 blocks myeloid differentiation of 32Dcl3 cells induced by granulocyte colony-stimulating factor. Taken together, it is suggested that one of the mechanisms for AML1/Evi-1-associated leukemogenesis should be an aberrant recruitment of a corepressor complex by the chimeric protein.
Izutsu
Koji
K
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Kurokawa
Mineo
M
Imai
Yoichi
Y
Ichikawa
Motoshi
M
Asai
Takashi
T
Maki
Kazuhiro
K
Mitani
Kinuko
K
Hirai
Hisamaru
H
D000429:Alcohol Oxidoreductases; D000818:Animals; D019677:Artificial Gene Fusion; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes; D012313:RNA / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014158:Transcription, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D012313:RNA; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D006655:Histone Deacetylases