title: The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion.
abstract: The NUP98 gene is involved in 3 distinct chromosomal rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and inv(11)(p15q22); all of these NUP98 rearrangements have been identified in the malignant cells of patients with therapy-related acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS). Here we report the cloning and characterization of a t(11;20)(p15;q11) translocation from patients with t-MDS. The breakpoint on chromosome 11p15 targets the NUP98 gene and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C-terminus. The breakpoint on chromosome 20q11 occurs within the gene encoding human DNA topoisomerase I (TOP1). As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced. These results indicate that NUP98 is a recurrent target in therapy-related malignancies, and that TOP1 is a previously unrecognized target for chromosomal translocations.
authors.affiliation: Departments of Medicine, Pediatrics, and Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Ahuja
authors.forename: C A
authors.initials: CA
authors.lastname: Felix
authors.forename: P D
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001483:Base Sequence; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D002890:Chromosomes, Human, Pair 20; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D014178:Translocation, Genetic
chemical_list: D008565:Membrane Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C093350:nuclear pore complex protein 98; D004264:DNA Topoisomerases, Type I