title: Microhomologies and topoisomerase II consensus sequences identified near the breakpoint junctions of the recurrent t(7;21)(p22;q22) translocation in acute myeloid leukemia.
abstract: RUNX1 rearrangements are common genetic abnormalities in acute leukemia. The t(7;21)(p22;q22) translocation, recently described in three cases of myeloid neoplasias, fuses the ubiquitin specific peptidase 42 gene, USP42, a member of the deubiquitinating enzyme family, to RUNX1. In this study, we characterized the semicryptic t(7;21)(p22;q22) translocation, identified by fluorescent in situ hybridization and spectral karyotyping, in a novel case of acute myeloid leukemia. Sequence analysis of the reverse transcription-polymerase chain reaction products confirmed the presence of two in-frame RUNX1-USP42 and one reciprocal in-frame USP42-RUNX1 fusion transcripts. Bioinformatic analysis of the genomic translocation breakpoints revealed microhomologies and insertion of shared nucleotides at the junctions. A topoisomerase II sequence was also detected near the break site. Additionally, we demonstrated a significant overexpression of the rearranged USP42 gene in t(7;21) positive cells using quantitative real-time PCR. Our results provide the first evidence of the possible involvement of the nonhomologous end-joining mechanism in the origin of the recurrent t(7;21) translocation. Moreover, presence of the complete catalytic USP site in the putative chimeric proteins and the upregulated expression of USP42 suggest a role of the deubiquitinating enzyme in the pathogenesis of this leukemia.
authors.affiliation: Quebec Leukemia Cell Bank and Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada, H1T 2M4; Department of Medicine, University of Montreal, Quebec, Canada, H3C 3J7.
authors.forename: Amélie
authors.initials: A
authors.lastname: Giguère
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics; D001483:Base Sequence; D056905:Chromosome Breakpoints; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D050506:Mutant Chimeric Proteins / Q000235:genetics; D013869:Thiolester Hydrolases / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D000951:Antigens, Neoplasm; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D050506:Mutant Chimeric Proteins; C493728:RUNX1 protein, human; C508707:USP42 protein, human; D013869:Thiolester Hydrolases; D004250:DNA Topoisomerases, Type II