title: The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties.
abstract: The (3;21)(q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the alpha subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the beta subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression prevented tumor growth. These results suggest that expression of AML1/EAP and AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line.
authors.affiliation: Department of Medicine, University of Chicago, IL 60637, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Zent
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.forename: D F
authors.initials: DF
authors.lastname: Claxton
authors.forename: D E
authors.initials: DE
authors.lastname: Zhang
authors.forename: D G
authors.initials: DG
authors.lastname: Tenen
authors.forename: J D
authors.initials: JD
authors.lastname: Rowley
authors.forename: G
authors.initials: G
authors.lastname: Nucifora
mesh_terms: D000208:Acute Disease; D000818:Animals; D001752:Blast Crisis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002678:Chimera; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D002893:Chromosomes, Human, Pair 3; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012269:Ribosomal Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C493728:RUNX1 protein, human; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012269:Ribosomal Proteins; C489369:Rpl22 protein, rat; C493726:Runx1 protein, mouse; C493727:Runx1 protein, rat; D014157:Transcription Factors; C067169:RPL22 protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3