title: Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15).
abstract: The t(11;20)(p15;q11) is a rare but recurrent translocation that so far has been described in only four acute myeloid leukemias (AMLs), two treatment-related myelodysplastic syndromes (t-MDSs), and one case of polycythemia vera. Recently, the t(11;20) was shown to result in a fusion of the NUP98 and TOP1 genes, with expression of the NUP98/TOP1 chimera encoded by the der(11)t(11;20), but not of the reciprocal TOP1/NUP98 on the der(20)t(11;20). The genomic breakpoints were subsequently mapped to introns 13 and 7 of NUP98 and TOP1, respectively. We present here a t-MDS with a three-way variant translocation, t(10;20;11)(q24;q11;p15), that generates a der(11)t(11;20) but not a der(20)t(11;20), strongly suggesting that the der(11) harbors the critical genetic rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a NUP98/TOP1 fusion in which exon 13 of NUP98 was fused in-frame with exon 8 of TOP1. Extra long (XL) genomic PCR and subsequent sequence analyses showed that the breakpoint in NUP98 occurred at nucleotide (nt) 3461 of intron 13, close to a MER (medium reiteration frequency interspersed repetitive element) repeat, and that the breakpoint in TOP1 was at nt 1436 of intron 7, downstream of a MIR (mammalian-wide interspersed repeats) repetitive element. Genomic XL PCR did not amplify the reciprocal TOP1/NUP98, nor was this chimera expressed, as expected from the cytogenetic finding. The present results provide further support for the involvement of the NUP98/TOP1 transcript, but not of the reciprocal one, in the development of MDS/AML. Furthermore, the three cases genomically characterized to date have all been treatment-related and have all harbored breakpoints in intron 13 of NUP98 and intron 7 of TOP1, suggesting that these introns are susceptible to chemotherapy-induced breakage.
authors.affiliation: Department of Clinical Genetics, University Hospital, Lund, Sweden. ioannis.panagopoulos@klingen.lu.se
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagopoulos
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.forename: Margareth
authors.initials: M
authors.lastname: Isaksson
authors.forename: Gun
authors.initials: G
authors.lastname: Larsson
authors.forename: Rolf
authors.initials: R
authors.lastname: Billström
authors.forename: Felix
authors.initials: F
authors.lastname: Mitelman
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000096:biosynthesis* / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; C093350:nuclear pore complex protein 98; D004264:DNA Topoisomerases, Type I