title: AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1.
abstract: The t(3;21) chromosomal translocation seen in blastic crisis of chronic myeloid leukemia and secondary leukemias results in a formation of a chimeric protein AML1-Evi-1, which suppresses wild-type AML1 function. Loss of AML1 function causes expansion of hematopoietic progenitor cells, whereas it is not sufficient for the development of leukemia. To identify essential mechanisms through which AML1-Evi-1 exerts full leukemogenic potential, we introduced AML1-Evi-1 and its mutants in murine bone marrow cells, and evaluated their transforming activities by colony replating assays. The transforming activity of AML1-Evi-1 was lost when any of the known functional domains of Evi-1 was deleted from the chimeric protein, and forced expression of Evi-1 did not transform the AML1-deleted bone marrow cells. Unlike the MLL-ENL and AML1-ETO leukemia-related chimeric proteins, AML1-Evi-1 could transform only the hematopoietic stem cell fraction. Moreover, AML1-Evi-1-transformed cells show a cell-marker profile distinct from that of the cells transformed by AML1-ETO, which also suppresses AML1 function. Thus, leukemogenic activity of AML1-Evi-1 may be due to activation of molecular mechanisms distinct from those activated by MLL-ENL or AML1-ETO in the hematopoietic stem cell fractions.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takeshita
authors.forename: M
authors.initials: M
authors.lastname: Ichikawa
authors.forename: E
authors.initials: E
authors.lastname: Nitta
authors.forename: S
authors.initials: S
authors.lastname: Goyama
authors.forename: T
authors.initials: T
authors.lastname: Asai
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Chiba
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells; D019426:Integrases / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D023461:Myeloid Progenitor Cells / Q000502:physiology; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011519:Proto-Oncogenes / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit; C045073:Cre recombinase; D019426:Integrases