title: Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3;21) leukemias.
abstract: The chromosomal translocation t(3;21)(q26;q22), which is found in blastic crisis in chronic myelogenous leukemias and myelodysplastic syndrome-derived leukemias, produces AML1/Evi-1 chimeric transcription factor and is thought to play important roles in acute leukemic transformation of hemopoietic stem cells. We report here the functional analyses of AML1/Evi-1. It was revealed that AML1/Evi-1 itself does not alter the transactivation level through mouse polyomavirus enhancer-binding protein 2 (PEBP2; PEA2) sites (binding site of AML1) but dominantly suppresses the transactivation by intact AML1, which is assumed to be a stimulator of myeloid cell differentiation. DNA-binding competition is a putative mechanism of such dominant negative effects of AML1/Evi-1 because it binds to PEBP2 sites with higher affinity than AML1 does. Furthermore, AML1/Evi-1 stimulated c-fos promoter transactivation and increased AP-1 activity, as Evi-1 (which is not normally expressed in hemopoietic cells) did. Experiments using deletion mutants of AML1/Evi-1 showed that these two functions are mutually independent because the dominant negative effects on intact AML1 and the stimulation of AP-1 activity are dependent on the runt domain (DNA-binding domain of AML1) and the zinc finger domain near the C terminus, respectively. Furthermore, we showed that AML1/Evi-1 blocks granulocytic differentiation, otherwise induced by granulocyte colony-stimulating factor, of 32Dcl3 myeloid cells. It was also suggested that both AML1-derived and Evi-1-derived portions of the fusion protein play crucial roles in this differentiation block. We conclude that the leukemic cell transformation in t(3;21) leukemias is probably caused by these dual functions of AML1/Evi-1 chimeric protein.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Mitani
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: J
authors.initials: J
authors.lastname: Nishida
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Shibata
authors.forename: H
authors.initials: H
authors.lastname: Hirai
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D002893:Chromosomes, Human, Pair 3; D050676:Core Binding Factor Alpha 2 Subunit; D015342:DNA Probes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015342:DNA Probes; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; D018808:Transcription Factor AP-1; D014157:Transcription Factors