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.